Biochemistry, Genetics and Molecular Biology › Genetics

Estrogen and related hormone effects

Works Count: 111455

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Description

This cluster of papers explores the mechanisms of estrogen receptor signaling, with a focus on its role in breast cancer, interactions with glucocorticoids, and the effects of various drugs such as tamoxifen and aromatase inhibitors. It delves into the molecular pathways, gene regulation, and coactivator/coregulator dynamics involved in estrogen signaling.

Keywords

Estrogen; Receptor; Signaling; Breast Cancer; Glucocorticoids; Nuclear Receptors; Tamoxifen; Aromatase Inhibitors; G Protein-Coupled Receptor; Transcriptional Regulation

Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial

2002-06-01

M Baum , Aman U. Budzar , J Cuzick +4 more

A signature motif in transcriptional co-activators mediates binding to nuclear receptors

1997-06-01

David M. Heery , Eric Kalkhoven , Susan Hoare +1 more

Endogenous Sex Hormones and Breast Cancer in Postmenopausal Women: Reanalysis of Nine Prospective Studies

2002-04-17

Timothy J. Key , P N Appleby , Isobel Barnes +1 more

Background: Reproductive and hormonal factors are involved in the etiology of breast cancer, but there are only a few prospective studies on endogenous sex hormone levels and breast cancer risk. … Background: Reproductive and hormonal factors are involved in the etiology of breast cancer, but there are only a few prospective studies on endogenous sex hormone levels and breast cancer risk. We reanalyzed the worldwide data from prospective studies to examine the relationship between the levels of endogenous sex hormones and breast cancer risk in postmenopausal women. Methods: We analyzed the individual data from nine prospective studies on 663 women who developed breast cancer and 1765 women who did not. None of the women was taking exogenous sex hormones when their blood was collected to determine hormone levels. The relative risks (RRs) for breast cancer associated with increasing hormone concentrations were estimated by conditional logistic regression on case–control sets matched within each study. Linear trends and heterogeneity of RRs were assessed by two-sided tests or chi-square tests, as appropriate. Results: The risk for breast cancer increased statistically significantly with increasing concentrations of all sex hormones examined: total estradiol, free estradiol, non-sex hormone-binding globulin (SHBG)-bound estradiol (which comprises free and albumin-bound estradiol), estrone, estrone sulfate, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone. The RRs for women with increasing quintiles of estradiol concentrations, relative to the lowest quintile, were 1.42 (95% confidence interval [CI] = 1.04 to 1.95), 1.21 (95% CI = 0.89 to 1.66), 1.80 (95% CI = 1.33 to 2.43), and 2.00 (95% CI = 1.47 to 2.71; Ptrend<.001); the RRs for women with increasing quintiles of free estradiol were 1.38 (95% CI = 0.94 to 2.03), 1.84 (95% CI = 1.24 to 2.74), 2.24 (95% CI = 1.53 to 3.27), and 2.58 (95% CI = 1.76 to 3.78; Ptrend<.001). The magnitudes of risk associated with the other estrogens and with the androgens were similar. SHBG was associated with a decrease in breast cancer risk (Ptrend = .041). The increases in risk associated with increased levels of all sex hormones remained after subjects who were diagnosed with breast cancer within 2 years of blood collection were excluded from the analysis. Conclusion: Levels of endogenous sex hormones are strongly associated with breast cancer risk in postmenopausal women.

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Tamoxifen for early breast cancer: an overview of the randomised trials

1998-05-01

Mike Clarke , R Collins , Claire Davies +3 more

A Transmembrane Intracellular Estrogen Receptor Mediates Rapid Cell Signaling

2005-02-11

Chetana M. Revankar , Daniel F. Cimino , Larry A. Sklar +2 more

The steroid hormone estrogen regulates many functionally unrelated processes in numerous tissues. Although it is traditionally thought to control transcriptional activation through the classical nuclear estrogen receptors, it also initiates … The steroid hormone estrogen regulates many functionally unrelated processes in numerous tissues. Although it is traditionally thought to control transcriptional activation through the classical nuclear estrogen receptors, it also initiates many rapid nongenomic signaling events. We found that of all G protein–coupled receptors characterized to date, GPR30 is uniquely localized to the endoplasmic reticulum, where it specifically binds estrogen and fluorescent estrogen derivatives. Activating GPR30 by estrogen resulted in intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus. Thus, GPR30 represents an intracellular transmembrane estrogen receptor that may contribute to normal estrogen physiology as well as pathophysiology.

Steroid hormone receptors: Many Actors in search of a plot

1995-12-01

Miguel Beato , Peter Herrlich , Günther Schütz

Transcriptional interference between c-Jun and the glucocorticoid receptor: Mutual inhibition of DNA binding due to direct protein-protein interaction

1990-09-01

Hsin‐Fang Yang‐Yen , Jean‐Claude Chambard , Yu-Lin Sun +4 more

Mechanisms involved in the side effects of glucocorticoids

2002-10-01

Heike Schäcke

Effects of Raloxifene on Bone Mineral Density, Serum Cholesterol Concentrations, and Uterine Endometrium in Postmenopausal Women

1997-12-04

Pierre D. Delmas , Nina H. Bjarnason , Bruce Mitlak +5 more

Long-term estrogen therapy can reduce the risk of osteoporotic fracture and cardiovascular disease in postmenopausal women. At present, however, these beneficial effects are not separable from undesirable stimulation of breast … Long-term estrogen therapy can reduce the risk of osteoporotic fracture and cardiovascular disease in postmenopausal women. At present, however, these beneficial effects are not separable from undesirable stimulation of breast and endometrial tissues.

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Primary structure and expression of a functional human glucocorticoid receptor cDNA

1985-12-01

Stanley M. Hollenberg , Cary Weinberger , Estelita S. Ong +6 more

Generation and reproductive phenotypes of mice lacking estrogen receptor β

1998-12-22

John H. Krege , Jeffrey B. Hodgin , John F. Couse +7 more

Estrogens influence the differentiation and maintenance of reproductive tissues and affect lipid metabolism and bone remodeling. Two estrogen receptors (ERs) have been identified to date, ERα and ERβ. We previously … Estrogens influence the differentiation and maintenance of reproductive tissues and affect lipid metabolism and bone remodeling. Two estrogen receptors (ERs) have been identified to date, ERα and ERβ. We previously generated and studied knockout mice lacking estrogen receptor α and reported severe reproductive and behavioral phenotypes including complete infertility of both male and female mice and absence of breast tissue development. Here we describe the generation of mice lacking estrogen receptor β (ERβ −/−) by insertion of a neomycin resistance gene into exon 3 of the coding gene by using homologous recombination in embryonic stem cells. Mice lacking this receptor develop normally and are indistinguishable grossly and histologically as young adults from their littermates. RNA analysis and immunocytochemistry show that tissues from ERβ −/− mice lack normal ERβ RNA and protein. Breeding experiments with young, sexually mature females show that they are fertile and exhibit normal sexual behavior, but have fewer and smaller litters than wild-type mice. Superovulation experiments indicate that this reduction in fertility is the result of reduced ovarian efficiency. The mutant females have normal breast development and lactate normally. Young, sexually mature male mice show no overt abnormalities and reproduce normally. Older mutant males display signs of prostate and bladder hyperplasia. Our results indicate that ERβ is essential for normal ovulation efficiency but is not essential for female or male sexual differentiation, fertility, or lactation. Future experiments are required to determine the role of ERβ in bone and cardiovascular homeostasis.

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Cloning of Human Mineralocorticoid Receptor Complementary DNA: Structural and Functional Kinship with the Glucocorticoid Receptor

1987-07-17

Jeffrey L. Arriza , Cary Weinberger , Gail Cerelli +4 more

Low-stringency hybridization with human glucocorticoid receptor (hGR) complementary DNA was used to isolate a new gene encoding a predicted 107-kilodalton polypeptide. Expression studies demonstrate its ability to bind aldosterone with … Low-stringency hybridization with human glucocorticoid receptor (hGR) complementary DNA was used to isolate a new gene encoding a predicted 107-kilodalton polypeptide. Expression studies demonstrate its ability to bind aldosterone with high affinity and to activate gene transcription in response to aldosterone, thus establishing its identity as the human mineralocorticoid receptor (hMR). This molecule also shows high affinity for glucocorticoids and stimulates a glucocorticoid-responsive promoter. Together the hMR and hGR provide unexpected functional diversity in which hormone-binding properties, target gene interactions, and patterns of tissue-specific expression may be used in a combinatorial fashion to achieve complex physiologic control.

Estrogen Carcinogenesis in Breast Cancer

2006-01-18

James D. Yager , Nancy E. Davidson

Estrogen exposure is a major determinant of the risk of breast cancer. This article reviews how genotoxic, mutagenic metabolites of estrogen and stimulation of tissue growth by the hormone participate … Estrogen exposure is a major determinant of the risk of breast cancer. This article reviews how genotoxic, mutagenic metabolites of estrogen and stimulation of tissue growth by the hormone participate in the pathogenesis of breast cancer.

Cofactor Dynamics and Sufficiency in Estrogen Receptor–Regulated Transcription

2000-12-01

Yongfeng Shang , Xiao Hu , James DiRenzo +2 more

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Gender Disparity in Liver Cancer Due to Sex Differences in MyD88-Dependent IL-6 Production

2007-07-06

Willscott E. Naugler , Toshiharu Sakurai , Sunhwa Kim +4 more

Hepatocellular carcinoma (HCC), the most common liver cancer, occurs mainly in men. Similar gender disparity is seen in mice given a chemical carcinogen, diethylnitrosamine (DEN). DEN administration caused greater increases … Hepatocellular carcinoma (HCC), the most common liver cancer, occurs mainly in men. Similar gender disparity is seen in mice given a chemical carcinogen, diethylnitrosamine (DEN). DEN administration caused greater increases in serum interleukin-6 (IL-6) concentration in males than it did in females. Furthermore, ablation of IL-6 abolished the gender differences in hepatocarcinogenesis in mice. DEN exposure promoted production of IL-6 in Kupffer cells (KCs) in a manner dependent on the Toll-like receptor adaptor protein MyD88, ablation of which also protected male mice from DEN-induced hepatocarcinogenesis. Estrogen inhibited secretion of IL-6 from KCs exposed to necrotic hepatocytes and reduced circulating concentrations of IL-6 in DEN-treated male mice. We propose that estrogen-mediated inhibition of IL-6 production by KCs reduces liver cancer risk in females, and these findings may be used to prevent HCC in males.

Interaction of Estrogenic Chemicals and Phytoestrogens with Estrogen Receptor β

1998-10-01

George G. J. M. Kuiper , Josephine G. Lemmen , Bo Carlsson +5 more

The rat, mouse and human estrogen receptor (ER) exists as two subtypes, ER alpha and ER beta, which differ in the C-terminal ligand-binding domain and in the N-terminal transactivation domain. … The rat, mouse and human estrogen receptor (ER) exists as two subtypes, ER alpha and ER beta, which differ in the C-terminal ligand-binding domain and in the N-terminal transactivation domain. In this study, we investigated the estrogenic activity of environmental chemicals and phytoestrogens in competition binding assays with ER alpha or ER beta protein, and in a transient gene expression assay using cells in which an acute estrogenic response is created by cotransfecting cultures with recombinant human ER alpha or ER beta complementary DNA (cDNA) in the presence of an estrogen-dependent reporter plasmid. Saturation ligand-binding analysis of human ER alpha and ER beta protein revealed a single binding component for [3H]-17beta-estradiol (E2) with high affinity [dissociation constant (Kd) = 0.05 - 0.1 nM]. All environmental estrogenic chemicals [polychlorinated hydroxybiphenyls, dichlorodiphenyltrichloroethane (DDT) and derivatives, alkylphenols, bisphenol A, methoxychlor and chlordecone] compete with E2 for binding to both ER subtypes with a similar preference and degree. In most instances the relative binding affinities (RBA) are at least 1000-fold lower than that of E2. Some phytoestrogens such as coumestrol, genistein, apigenin, naringenin, and kaempferol compete stronger with E2 for binding to ER beta than to ER alpha. Estrogenic chemicals, as for instance nonylphenol, bisphenol A, o, p'-DDT and 2',4',6'-trichloro-4-biphenylol stimulate the transcriptional activity of ER alpha and ER beta at concentrations of 100-1000 nM. Phytoestrogens, including genistein, coumestrol and zearalenone stimulate the transcriptional activity of both ER subtypes at concentrations of 1-10 nM. The ranking of the estrogenic potency of phytoestrogens for both ER subtypes in the transactivation assay is different; that is, E2 >> zearalenone = coumestrol > genistein > daidzein > apigenin = phloretin > biochanin A = kaempferol = naringenin > formononetin = ipriflavone = quercetin = chrysin for ER alpha and E2 >> genistein = coumestrol > zearalenone > daidzein > biochanin A = apigenin = kaempferol = naringenin > phloretin = quercetin = ipriflavone = formononetin = chrysin for ER beta. Antiestrogenic activity of the phytoestrogens could not be detected, except for zearalenone which is a full agonist for ER alpha and a mixed agonist-antagonist for ER beta. In summary, while the estrogenic potency of industrial-derived estrogenic chemicals is very limited, the estrogenic potency of phytoestrogens is significant, especially for ER beta, and they may trigger many of the biological responses that are evoked by the physiological estrogens.

Estrogen Receptor Null Mice: What Have We Learned and Where Will They Lead Us?

1999-06-01

John F. Couse , Kenneth S. Korach

All scientific investigations begin with distinct objectives: first is the hypothesis upon which studies are undertaken to disprove, and second is the overall aim of obtaining further information, from which … All scientific investigations begin with distinct objectives: first is the hypothesis upon which studies are undertaken to disprove, and second is the overall aim of obtaining further information, from which future and more precise hypotheses may be drawn. Studies focusing on the generation and use of gene-targeted animal models also apply these goals and may be loosely categorized into sequential phases that become apparent as the use of the model progresses. Initial studies of knockout models often focus on the plausibility of the model based on prior knowledge and whether the generation of an animal lacking the particular gene will prove lethal or not. Upon the successful generation of a knockout, confirmatory studies are undertaken to corroborate previously established hypotheses of the function of the disrupted gene product. As these studies continue, observations of unpredicted phenotypes or, more likely, the lack of a phenotype that was expected based on models put forth from past investigations are noted. Often the surprising phenotype is due to the loss of a gene product that is downstream from the functions of the disrupted gene, whereas the lack of an expected phenotype may be due to compensatory roles filled by alternate mechanisms. As the descriptive studies of the knockout continue, use of the model is often shifted to the role as a unique research reagent, to be used in studies that 1) were not previously possible in a wild-type model; 2) aimed at finding related proteins or pathways whose existence or functions were previously masked; or 3) the subsequent effects of the gene disruption on related physiological and biochemical systems. The alpha ERKO mice continue to satisfy the confirmatory role of a knockout quite well. As summarized in Table 4, the phenotypes observed in the alpha ERKO due to estrogen insensitivity have definitively illustrated several roles that were previously believed to be dependent on functional ER alpha, including 1) the proliferative and differentiative actions critical to the function of the adult female reproductive tract and mammary gland; 2) as an obligatory component in growth factor signaling in the uterus and mammary gland; 3) as the principal steroid involved in negative regulation of gonadotropin gene transcription and LH levels in the hypothalamic-pituitary axis; 4) as a positive regulator of PR expression in several tissues; 5) in the positive regulation of PRL synthesis and secretion from the pituitary; 6) as a promotional factor in oncogene-induced mammary neoplasia; and 7) as a crucial component in the differentiation and activation of several behaviors in both the female and male. The list of unpredictable phenotypes in the alpha ERKO must begin with the observation that generation of an animal lacking a functional ER alpha gene was successful and produced animals of both sexes that exhibit a life span comparable to wild-type. The successful generation of beta ERKO mice suggests that this receptor is also not essential to survival and was most likely not a compensatory factor in the survival of the alpha ERKO. In support of this is our recent successful generation of double knockout, or alpha beta ERKO mice of both sexes. The precise defects in certain components of male reproduction, including the production of abnormal sperm and the loss of intromission and ejaculatory responses that were observed in the alpha ERKO, were quite surprising. In turn, certain estrogen pathways in the alpha ERKO female appear intact or unaffected, such as the ability of the uterus to successfully exhibit a progesterone-induced decidualization response, and the possible maintenance of an LH surge system in the hypothalamus. [ABSTRACT TRUNCATED]

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AIB1, a Steroid Receptor Coactivator Amplified in Breast and Ovarian Cancer

1997-08-15

Sarah L. Anzick , Juha Kononen , Robert L. Walker +7 more

Members of the recently recognized SRC-1 family of transcriptional coactivators interact with steroid hormone receptors to enhance ligand-dependent transcription. AIB1, a member of the SRC-1 family, was cloned during a … Members of the recently recognized SRC-1 family of transcriptional coactivators interact with steroid hormone receptors to enhance ligand-dependent transcription. AIB1, a member of the SRC-1 family, was cloned during a search on the long arm of chromosome 20 for genes whose expression and copy number were elevated in human breast cancers. AIB1 amplification and overexpression were observed in four of five estrogen receptor-positive breast and ovarian cancer cell lines. Subsequent evaluation of 105 unselected specimens of primary breast cancer found AIB1 amplification in approximately 10 percent and high expression in 64 percent of the primary tumors analyzed. AIB1 protein interacted with estrogen receptors in a ligand-dependent fashion, and transfection of AIB1 resulted in enhancement of estrogen-dependent transcription. These observations identify AIB1 as a nuclear receptor coactivator whose altered expression may contribute to development of steroid-dependent cancers.

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Gene regulation by steroid hormones

1989-02-01

Miguel Beato

Sequence and Characterization of a Coactivator for the Steroid Hormone Receptor Superfamily

1995-11-24

Sergio A. Oñate , Sophia Y. Tsai , Ming‐Jer Tsai +1 more

A yeast two-hybrid system was used to identify a protein that interacts with and enhances the human progesterone receptor (hPR) transcriptional activity without altering the basal activity of the promoter. … A yeast two-hybrid system was used to identify a protein that interacts with and enhances the human progesterone receptor (hPR) transcriptional activity without altering the basal activity of the promoter. Because the protein stimulated transactivation of all the steroid receptors tested, it has been termed steroid receptor coactivator-1 (SRC-1). Coexpression of SRC-1 reversed the ability of the estrogen receptor to squelch activation by hPR. Also, the amino terminal truncated form of SRC-1 acted as a dominant-negative repressor. Together, these results indicate that SRC-1 encodes a coactivator that is required for full transcriptional activity of the steroid receptor superfamily.

Activation of the Estrogen Receptor Through Phosphorylation by Mitogen-Activated Protein Kinase

1995-12-01

Shigeaki Kato , Hideki Endoh , Yoshikazu Masuhiro +7 more

The phosphorylation of the human estrogen receptor (ER) serine residue at position 118 is required for full activity of the ER activation function 1 (AF-1). This Ser 118 is phosphorylated … The phosphorylation of the human estrogen receptor (ER) serine residue at position 118 is required for full activity of the ER activation function 1 (AF-1). This Ser 118 is phosphorylated by mitogen-activated protein kinase (MAPK) in vitro and in cells treated with epidermal growth factor (EGF) and insulin-like growth factor (IGF) in vivo. Overexpression of MAPK kinase (MAPKK) or of the guanine nucleotide binding protein Ras, both of which activate MAPK, enhanced estrogen-induced and antiestrogen (tamoxifen)-induced transcriptional activity of wild-type ER, but not that of a mutant ER with an alanine in place of Ser 118 . Thus, the activity of the amino-terminal AF-1 of the ER is modulated by the phosphorylation of Ser 118 through the Ras-MAPK cascade of the growth factor signaling pathways.

Cloning of a novel receptor expressed in rat prostate and ovary.

1996-06-11

George G. J. M. Kuiper , Eva Enmark , Markku Pelto‐Huikko +2 more

We have cloned a novel member of the nuclear receptor superfamily. The cDNA of clone 29 was isolated from a rat prostate cDNA library and it encodes a protein of … We have cloned a novel member of the nuclear receptor superfamily. The cDNA of clone 29 was isolated from a rat prostate cDNA library and it encodes a protein of 485 amino acid residues with a calculated molecular weight of 54.2 kDa. Clone 29 protein is unique in that it is highly homologous to the rat estrogen receptor (ER) protein, particularly in the DNA-binding domain (95%) and in the C-terminal ligand-binding domain (55%). Expression of clone 29 in rat tissues was investigated by in situ hybridization and prominent expression was found in prostate and ovary. In the prostate clone 29 is expressed in the epithelial cells of the secretory alveoli, whereas in the ovary the granuloma cells in primary, secondary, and mature follicles showed expression of clone 29. Saturation ligand-binding analysis of in vitro synthesized clone 29 protein revealed a single binding component for 17beta-estradiol (E2) with high affinity (Kd= 0.6 nM). In ligand-competition experiments the binding affinity decreased in the order E2 > diethylstilbestrol > estriol > estrone > 5alpha-androstane-3beta,17beta-diol >> testosterone = progesterone = corticosterone = 5alpha-androstane-3alpha,17beta-diol. In cotransfection experiments of Chinese hamster ovary cells with a clone 29 expression vector and an estrogen-regulated reporter gene, maximal stimulation (about 3-fold) of reporter gene activity was found during incubation with 10 nM of E2. Neither progesterone, testosterone, dexamethasone, thyroid hormone, all-trans-retinoic acid, nor 5alpha-androstane-3alpha,I7beta-diol could stimulate reporter gene activity, whereas estrone and 5alpha-androstane-3beta,17beta-diol did. We conclude that clone 29 cDNA encodes a novel rat ER, which we suggest be named rat ERbeta to distinguish it from the previously cloned ER (ERalpha) from rat uterus.

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Comparison of the Ligand Binding Specificity and Transcript Tissue Distribution of Estrogen Receptors α and β

1997-03-01

George G. J. M. Kuiper , Bo Carlsson , Kaj Grandien +4 more

Abstract The rat estrogen receptor (ER) exists as two subtypes, ERα and ERβ, which differ in the C-terminal ligand binding domain and in the N-terminal transactivation domain. In this study … Abstract The rat estrogen receptor (ER) exists as two subtypes, ERα and ERβ, which differ in the C-terminal ligand binding domain and in the N-terminal transactivation domain. In this study we investigated the messenger RNA expression of both ER subtypes in rat tissues by RT-PCR and compared the ligand binding specificity of the ER subtypes. Saturation ligand binding analysis of in vitro synthesized human ERα and rat ERβ protein revealed a single binding component for 16α-iodo-17β-estradiol with high affinity[ dissociation constant (Kd) = 0.1 nm for ERα protein and 0.4 nm for ERβ protein]. Most estrogenic substances or estrogenic antagonists compete with 16α-[125I]iodo-17β-estradiol for binding to both ER subtypes in a very similar preference and degree; that is, diethylstilbestrol &gt; hexestrol &gt; dienestrol &gt; 4-OH-tamoxifen &gt; 17β-estradiol &gt; coumestrol, ICI-164384 &gt; estrone, 17α-estradiol &gt; nafoxidine, moxestrol &gt; clomifene &gt; estriol, 4-OH-estradiol &gt; tamoxifen, 2-OH-estradiol, 5-androstene-3β,17β-diol, genistein for the ERα protein and dienestrol &gt; 4-OH-tamoxifen &gt; diethylstilbestrol &gt; hexestrol &gt; coumestrol, ICI-164384 &gt; 17β-estradiol &gt; estrone, genistein &gt; estriol &gt; nafoxidine, 5-androstene-3β,17β-diol &gt; 17α-estradiol, clomifene, 2-OH-estradiol &gt; 4-OH-estradiol, tamoxifen, moxestrol for the ERβ protein. The rat tissue distribution and/or the relative level of ERα and ERβ expression seems to be quite different, i.e. moderate to high expression in uterus, testis, pituitary, ovary, kidney, epididymis, and adrenal for ERα and prostate, ovary, lung, bladder, brain, uterus, and testis for ERβ. The described differences between the ER subtypes in relative ligand binding affinity and tissue distribution could contribute to the selective action of ER agonists and antagonists in different tissues.

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Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities.

1995-09-15

John P. Lydon , Francesco J. DeMayo , C. Funk +6 more

Although progesterone has been recognized as essential for the establishment and maintenance of pregnancy, this steroid hormone has been recently implicated to have a functional role in a number of … Although progesterone has been recognized as essential for the establishment and maintenance of pregnancy, this steroid hormone has been recently implicated to have a functional role in a number of other reproductive events. The physiological effects of progesterone are mediated by the progesterone receptor (PR), a member of the nuclear receptor superfamily of transcription factors. In most cases the PR is induced by estrogen, implying that many of the in vivo effects attributed to progesterone could also be the result of concomitantly administered estrogen. Therefore, to clearly define those physiological events that are specifically attributable to progesterone in vivo, we have generated a mouse model carrying a null mutation of the PR gene using embryonic stem cell/gene targeting techniques. Male and female embryos homozygous for the PR mutation developed normally to adulthood. However, the adult female PR mutant displayed significant defects in all reproductive tissues. These included an inability to ovulate, uterine hyperplasia and inflammation, severely limited mammary gland development, and an inability to exhibit sexual behavior. Collectively, these results provide direct support for progesterone's role as a pleiotropic coordinator of diverse reproductive events that together ensure species survival.

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Nuclear Receptor Coregulators: Cellular and Molecular Biology*

1999-06-01

Neil J. McKenna , Rainer B. Lanz , Bert W. O’Malley

Nuclear receptor coregulators are coactivators or corepressors that are required by nuclear receptors for efficient transcripitonal regulation. In this context, we define coactivators, broadly, as molecules that interact with nuclear … Nuclear receptor coregulators are coactivators or corepressors that are required by nuclear receptors for efficient transcripitonal regulation. In this context, we define coactivators, broadly, as molecules that interact with nuclear receptors and enhance their transactivation. Analogously, we refer to nuclear receptor corepressors as factors that interact with nuclear receptors and lower the transcription rate at their target genes. Most coregulators are, by definition, rate limiting for nuclear receptor activation and repression, but do not significantly alter basal transcription. Recent data have indicated multiple modes of action of coregulators, including direct interactions with basal transcription factors and covalent modification of histones and other proteins. Reflecting this functional diversity, many coregulators exist in distinct steady state precomplexes, which are thought to associate in promoter-specific configurations. In addition, these factors may function as molecular gates to enable integration of diverse signal transduction pathways at nuclear receptor-regulated promoters. This review will summarize selected aspects of our current knowledge of the cellular and molecular biology of nuclear receptor coregulators.

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Antitumor promotion and antiinflammation: Down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone

1990-09-01

Carsten Jonat , Hans J. Rahmsdorf , Kun-Koo Park +4 more

Molecular basis of agonism and antagonism in the oestrogen receptor

1997-10-01

A.M. Brzozowski , A.C.W. Pike , Zbigniew Dauter +7 more

A Randomized Trial of Letrozole in Postmenopausal Women after Five Years of Tamoxifen Therapy for Early-Stage Breast Cancer

2003-11-06

Paul E. Goss , James N. Ingle , Silvana Martino +7 more

In hormone-dependent breast cancer, five years of postoperative tamoxifen therapy--but not tamoxifen therapy of longer duration--prolongs disease-free and overall survival. The aromatase inhibitor letrozole, by suppressing estrogen production, might improve … In hormone-dependent breast cancer, five years of postoperative tamoxifen therapy--but not tamoxifen therapy of longer duration--prolongs disease-free and overall survival. The aromatase inhibitor letrozole, by suppressing estrogen production, might improve the outcome after the discontinuation of tamoxifen therapy.We conducted a double-blind, placebo-controlled trial to test the effectiveness of five years of letrozole therapy in postmenopausal women with breast cancer who have completed five years of tamoxifen therapy. The primary end point was disease-free survival.A total of 5187 women were enrolled (median follow-up, 2.4 years). At the first interim analysis, there were 207 local or metastatic recurrences of breast cancer or new primary cancers in the contralateral breast--75 in the letrozole group and 132 in the placebo group--with estimated four-year disease-free survival rates of 93 percent and 87 percent, respectively, in the two groups (P< or =0.001 for the comparison of disease-free survival). A total of 42 women in the placebo group and 31 women in the letrozole group died (P=0.25 for the comparison of overall survival). Low-grade hot flashes, arthritis, arthralgia, and myalgia were more frequent in the letrozole group, but vaginal bleeding was less frequent. There were new diagnoses of osteoporosis in 5.8 percent of the women in the letrozole group and 4.5 percent of the women in the placebo group (P=0.07); the rates of fracture were similar. After the first interim analysis, the independent data and safety monitoring committee recommended termination of the trial and prompt communication of the results to the participants.As compared with placebo, letrozole therapy after the completion of standard tamoxifen treatment significantly improves disease-free survival.

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Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes<SUBTITLE>The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial</SUBTITLE>

2006-06-06

Victor G. Vogel

ContextTamoxifen is approved for the reduction of breast cancer risk, and raloxifene has demonstrated a reduced risk of breast cancer in trials of older women with osteoporosis.ObjectiveTo compare the relative … ContextTamoxifen is approved for the reduction of breast cancer risk, and raloxifene has demonstrated a reduced risk of breast cancer in trials of older women with osteoporosis.ObjectiveTo compare the relative effects and safety of raloxifene and tamoxifen on the risk of developing invasive breast cancer and other disease outcomes.Design, Setting, and PatientsThe National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene trial, a prospective, double-blind, randomized clinical trial conducted beginning July 1, 1999, in nearly 200 clinical centers throughout North America, with final analysis initiated after at least 327 incident invasive breast cancers were diagnosed. Patients were 19 747 postmenopausal women of mean age 58.5 years with increased 5-year breast cancer risk (mean risk, 4.03% [SD, 2.17%]). Data reported are based on a cutoff date of December 31, 2005.InterventionOral tamoxifen (20 mg/d) or raloxifene (60 mg/d) over 5 years.Main Outcome MeasuresIncidence of invasive breast cancer, uterine cancer, noninvasive breast cancer, bone fractures, thromboembolic events.ResultsThere were 163 cases of invasive breast cancer in women assigned to tamoxifen and 168 in those assigned to raloxifene (incidence, 4.30 per 1000 vs 4.41 per 1000; risk ratio [RR], 1.02; 95% confidence interval [CI], 0.82-1.28). There were fewer cases of noninvasive breast cancer in the tamoxifen group (57 cases) than in the raloxifene group (80 cases) (incidence, 1.51 vs 2.11 per 1000; RR, 1.40; 95% CI, 0.98-2.00). There were 36 cases of uterine cancer with tamoxifen and 23 with raloxifene (RR, 0.62; 95% CI, 0.35-1.08). No differences were found for other invasive cancer sites, for ischemic heart disease events, or for stroke. Thromboembolic events occurred less often in the raloxifene group (RR, 0.70; 95% CI, 0.54-0.91). The number of osteoporotic fractures in the groups was similar. There were fewer cataracts (RR, 0.79; 95% CI, 0.68-0.92) and cataract surgeries (RR, 0.82; 95% CI, 0.68-0.99) in the women taking raloxifene. There was no difference in the total number of deaths (101 vs 96 for tamoxifen vs raloxifene) or in causes of death.ConclusionsRaloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer. The risk of other cancers, fractures, ischemic heart disease, and stroke is similar for both drugs.Trial Registrationclinicaltrials.gov Identifier: NCT00003906Published online June 5, 2006 (doi:10.1001/jama.295.23.joc60074).

The Structural Basis of Estrogen Receptor/Coactivator Recognition and the Antagonism of This Interaction by Tamoxifen

1998-12-01

Andrew K. Shiau , D. Barstad , Paula M. Loria +4 more

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Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial

2010-11-18

Jack Cuzick , Ivana Šestak , Michael Baum +4 more

Estrogen Receptors: How Do They Signal and What Are Their Targets

2007-07-01

Nina Heldring , A.C.W. Pike , Sandra Andersson +7 more

During the past decade there has been a substantial advance in our understanding of estrogen signaling both from a clinical as well as a preclinical perspective. Estrogen signaling is a … During the past decade there has been a substantial advance in our understanding of estrogen signaling both from a clinical as well as a preclinical perspective. Estrogen signaling is a balance between two opposing forces in the form of two distinct receptors (ERα and ERβ) and their splice variants. The prospect that these two pathways can be selectively stimulated or inhibited with subtype-selective drugs constitutes new and promising therapeutic opportunities in clinical areas as diverse as hormone replacement, autoimmune diseases, prostate and breast cancer, and depression. Molecular biological, biochemical, and structural studies have generated information which is invaluable for the development of more selective and effective ER ligands. We have also become aware that ERs do not function by themselves but require a number of coregulatory proteins whose cell-specific expression explains some of the distinct cellular actions of estrogen. Estrogen is an important morphogen, and many of its proliferative effects on the epithelial compartment of glands are mediated by growth factors secreted from the stromal compartment. Thus understanding the cross-talk between growth factor and estrogen signaling is essential for understanding both normal and malignant growth. In this review we focus on several of the interesting recent discoveries concerning estrogen receptors, on estrogen as a morphogen, and on the molecular mechanisms of anti-estrogen signaling.

Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer

2005-01-01

Anthony Howell , Jack Cuzick , M Baum +7 more

Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene.

1993-12-01

Dennis B. Lubahn , Jeffrey S. Moyer , T S Golding +3 more

Estrogen receptor and its ligand, estradiol, have long been thought to be essential for survival, fertility, and female sexual differentiation and development. Consistent with this proposed crucial role, no human … Estrogen receptor and its ligand, estradiol, have long been thought to be essential for survival, fertility, and female sexual differentiation and development. Consistent with this proposed crucial role, no human estrogen receptor gene mutations are known, unlike the androgen receptor, where many loss of function mutations have been found. We have generated mutant mice lacking responsiveness to estradiol by disrupting the estrogen receptor gene by gene targeting. Both male and female animals survive to adulthood with normal gross external phenotypes. Females are infertile; males have a decreased fertility. Females have hypoplastic uteri and hyperemic ovaries with no detectable corpora lutea. In adult wild-type and heterozygous females, 3-day estradiol treatment at 40 micrograms/kg stimulates a 3- to 4-fold increase in uterine wet weight and alters vaginal cornification, but the uteri and vagina do not respond in the animals with the estrogen receptor gene disruption. Prenatal male and female reproductive tract development can therefore occur in the absence of estradiol receptor-mediated responsiveness.

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Estrogen replacement therapy and coronary heart disease: A quantitative assessment of the epidemiologic evidence

1991-01-01

Meir J. Stampfer , Graham A. Colditz

Comparative distribution of estrogen receptor-? and -? mRNA in the rat central nervous system

1997-12-01

Paul J. Shughrue , Malcolm V. Lane , István Merchenthaler

Estrogen plays a profound role in regulating the structure and function of many neuronal systems in the adult rat brain. The actions of estrogen were thought to be mediated by … Estrogen plays a profound role in regulating the structure and function of many neuronal systems in the adult rat brain. The actions of estrogen were thought to be mediated by a single nuclear estrogen receptor (ER) until the recent cloning of a novel ER (ER-beta). To ascertain which ER is involved in the regulation of different brain regions, the present study compared the distribution of the classical (ER-alpha) and novel (ER-beta) forms of ER mRNA-expressing neurons in the central nervous system (CNS) of the rat with in situ hybridization histochemistry. Female rat brain, spinal cord, and eyes were frozen, and cryostat sections were collected on slides, hybridized with [35S]-labeled antisense riboprobes complimentary to ER-alpha or ER-beta mRNA, stringently washed, and opposed to emulsion. The results of these studies revealed the presence of ER-alpha and ER-beta mRNA throughout the rostral-caudal extent of the brain and spinal cord. Neurons of the olfactory bulb, supraoptic, paraventricular, suprachiasmatic, and tuberal hypothalamic nuclei, zona incerta, ventral tegmental area, cerebellum (Purkinje cells), laminae III-V, VIII, and IX of the spinal cord, and pineal gland contained exclusively ER-beta mRNA. In contrast, only ER-alpha hybridization signal was seen in the ventromedial hypothalamic nucleus and subfornical organ. Perikarya in other brain regions, including the bed nucleus of the stria terminalis, medial and cortical amygdaloid nuclei, preoptic area, lateral habenula, periaqueductal gray, parabrachial nucleus, locus ceruleus, nucleus of the solitary tract, spinal trigeminal nucleus and superficial laminae of the spinal cord, contained both forms of ER mRNA. Although the cerebral cortex and hippocampus contained both ER mRNAs, the hybridization signal for ER-alpha mRNA was very weak compared with ER-beta mRNA. The results of these in situ hybridization studies provide detailed information about the distribution of ER-alpha and ER-beta mRNAs in the rat CNS. In addition, this comparative study provides evidence that the region-specific expression of ER-alpha, ER-beta, or both may be important in determining the physiological responses of neuronal populations to estrogen action.

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Multifactor-Dimensionality Reduction Reveals High-Order Interactions among Estrogen-Metabolism Genes in Sporadic Breast Cancer

2001-07-01

Marylyn D. Ritchie , Lance W. Hahn , Nady Roodi +4 more

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The coregulator exchange in transcriptional functions of nuclear receptors

2000-01-15

Christopher K. Glass , Michael G. Rosenfeld

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The Complex Role of Estrogens in Inflammation

2007-08-01

Rainer H. Straub

There is still an unresolved paradox with respect to the immunomodulating role of estrogens. On one side, we recognize inhibition of bone resorption and suppression of inflammation in several animal … There is still an unresolved paradox with respect to the immunomodulating role of estrogens. On one side, we recognize inhibition of bone resorption and suppression of inflammation in several animal models of chronic inflammatory diseases. On the other hand, we realize the immunosupportive role of estrogens in trauma/sepsis and the proinflammatory effects in some chronic autoimmune diseases in humans. This review examines possible causes for this paradox. This review delineates how the effects of estrogens are dependent on criteria such as: 1) the immune stimulus (foreign antigens or autoantigens) and subsequent antigen-specific immune responses (e.g., T cell inhibited by estrogens vs. activation of B cell); 2) the cell types involved during different phases of the disease; 3) the target organ with its specific microenvironment; 4) timing of 17β-estradiol administration in relation to the disease course (and the reproductive status of a woman); 5) the concentration of estrogens; 6) the variability in expression of estrogen receptor α and β depending on the microenvironment and the cell type; and 7) intracellular metabolism of estrogens leading to important biologically active metabolites with quite different anti- and proinflammatory function. Also mentioned are systemic supersystems such as the hypothalamic-pituitary-adrenal axis, the sensory nervous system, and the sympathetic nervous system and how they are influenced by estrogens. This review reinforces the concept that estrogens have antiinflammatory but also proinflammatory roles depending on above-mentioned criteria. It also explains that a uniform concept as to the action of estrogens cannot be found for all inflammatory diseases due to the enormous variable responses of immune and repair systems.

ERβ: Identification and characterization of a novel human estrogen receptor

1996-08-19

Sietse Mosselman , Jan Polman , R. Dijkema

A novel estrogen receptor (hereinafter referred to as ER beta) was cloned using degenerate PCR primers. A comparison of the amino acid sequence of ER beta with the "classical' ER … A novel estrogen receptor (hereinafter referred to as ER beta) was cloned using degenerate PCR primers. A comparison of the amino acid sequence of ER beta with the "classical' ER (ER alpha) shows a high degree of conservation of the DNA-binding domain (96%), and of the ligand-binding domain (58%). In contrast, the A/B domain, the hinge region and the F-domain are not conserved. Northern blot analysis revealed that ER beta is expressed in human thymus, spleen, ovary and testis. Transient transfections of an ER beta expression construct together with an ERE-based reporter construct in CHO cells clearly demonstrated transactivation of ER beta by 17 beta-estradiol. In addition, the ER alpha antagonist ICI-164384 is a potent antagonist for ER beta as well. Interestingly, the level of transactivation by 17 beta-estradiol is higher for ER alpha than for ER beta, which may reflect suboptimal conditions for ER beta at the level of the ligand, responsive element or cellular context.

Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial

2012-12-05

Christina Davies , Hongchao Pan , Jon Godwin +7 more

A Randomized Trial of Exemestane after Two to Three Years of Tamoxifen Therapy in Postmenopausal Women with Primary Breast Cancer

2004-03-10

R. Charles Coombes , Emma Hall , Lorna J. Gibson +7 more

Tamoxifen, taken for five years, is the standard adjuvant treatment for postmenopausal women with primary, estrogen-receptor-positive breast cancer. Despite this treatment, however, some patients have a relapse.We conducted a double-blind, … Tamoxifen, taken for five years, is the standard adjuvant treatment for postmenopausal women with primary, estrogen-receptor-positive breast cancer. Despite this treatment, however, some patients have a relapse.We conducted a double-blind, randomized trial to test whether, after two to three years of tamoxifen therapy, switching to exemestane was more effective than continuing tamoxifen therapy for the remainder of the five years of treatment. The primary end point was disease-free survival.Of the 4742 patients enrolled, 2362 were randomly assigned to switch to exemestane, and 2380 to continue to receive tamoxifen. After a median follow-up of 30.6 months, 449 first events (local or metastatic recurrence, contralateral breast cancer, or death) were reported--183 in the exemestane group and 266 in the tamoxifen group. The unadjusted hazard ratio in the exemestane group as compared with the tamoxifen group was 0.68 (95 percent confidence interval, 0.56 to 0.82; P<0.001 by the log-rank test), representing a 32 percent reduction in risk and corresponding to an absolute benefit in terms of disease-free survival of 4.7 percent (95 percent confidence interval, 2.6 to 6.8) at three years after randomization. Overall survival was not significantly different in the two groups, with 93 deaths occurring in the exemestane group and 106 in the tamoxifen group. Severe toxic effects of exemestane were rare. Contralateral breast cancer occurred in 20 patients in the tamoxifen group and 9 in the exemestane group (P=0.04).Exemestane therapy after two to three years of tamoxifen therapy significantly improved disease-free survival as compared with the standard five years of tamoxifen treatment.

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The Effect of Raloxifene on Risk of Breast Cancer in Postmenopausal Women

1999-06-16

Steven R. Cummings , Stephen Eckert , K A Krueger +7 more

ContextRaloxifene hydrochloride is a selective estrogen receptor modulator that has antiestrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipid metabolism, and blood clotting.ObjectiveTo determine whether women … ContextRaloxifene hydrochloride is a selective estrogen receptor modulator that has antiestrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipid metabolism, and blood clotting.ObjectiveTo determine whether women taking raloxifene have a lower risk of invasive breast cancer.Design and SettingThe Multiple Outcomes of Raloxifene Evaluation (MORE), a multicenter, randomized, double-blind trial, in which women taking raloxifene or placebo were followed up for a median of 40 months (SD, 3 years), from 1994 through 1998, at 180 clinical centers composed of community settings and medical practices in 25 countries, mainly in the United States and Europe.ParticipantsA total of 7705 postmenopausal women, younger than 81 (mean age, 66.5) years, with osteoporosis, defined by the presence of vertebral fractures or a femoral neck or spine T-score of at least 2.5 SDs below the mean for young healthy women. Almost all participants (96%) were white. Women who had a history of breast cancer or who were taking estrogen were excluded.InterventionRaloxifene, 60 mg, 2 tablets daily; or raloxifene, 60 mg, 1 tablet daily and 1 placebo tablet; or 2 placebo tablets.Main Outcome MeasuresNew cases of breast cancer, confirmed by histopathology. Transvaginal ultrasonography was used to assess the endometrial effects of raloxifene in 1781 women. Deep vein thrombosis or pulmonary embolism were determined by chart review.ResultsThirteen cases of breast cancer were confirmed among the 5129 women assigned to raloxifene vs 27 among the 2576 women assigned to placebo (relative risk [RR], 0.24; 95% confidence interval [CI], 0.13-0.44; P<.001). To prevent 1 case of breast cancer, 126 women would need to be treated. Raloxifene decreased the risk of estrogen receptor–positive breast cancer by 90% (RR, 0.10; 95% CI, 0.04-0.24), but not estrogen receptor–negative invasive breast cancer (RR, 0.88; 95% CI, 0.26-3.0). Raloxifene increased the risk of venous thromboembolic disease (RR, 3.1; 95% CI, 1.5-6.2), but did not increase the risk of endometrial cancer (RR, 0.8; 95% CI, 0.2-2.7).ConclusionAmong postmenopausal women with osteoporosis, the risk of invasive breast cancer was decreased by 76% during 3 years of treatment with raloxifene.

The nuclear receptor superfamily: The second decade

1995-12-01

David J. Mangelsdorf , Carl S. Thummel , Miguel Beato +7 more

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Mechanisms of Estrogen Action

2001-01-10

Stefan Nilsson , Sari Mäkelä , Eckardt Treuter +7 more

Our appreciation of the physiological functions of estrogens and the mechanisms through which estrogens bring about these functions has changed during the past decade. Just as transgenic mice were produced … Our appreciation of the physiological functions of estrogens and the mechanisms through which estrogens bring about these functions has changed during the past decade. Just as transgenic mice were produced in which estrogen receptors had been inactivated and we thought that we were about to understand the role of estrogen receptors in physiology and pathology, it was found that there was not one but two distinct and functional estrogen receptors, now called ERα and ERβ. Transgenic mice in which each of the receptors or both the receptors are inactive have revealed a much broader role for estrogens in the body than was previously thought. This decade also saw the description of a male patient who had no functional ERα and whose continued bone growth clearly revealed an important function of estrogen in men. The importance of estrogen in both males and females was also demonstrated in the laboratory in transgenic mice in which the aromatase gene was inactivated. Finally, crystal structures of the estrogen receptors with agonists and antagonists have revealed much about how ligand binding influences receptor conformation and how this conformation influences interaction of the receptor with coactivators or corepressors and hence determines cellular response to ligands.

[Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue].

1987-05-01

W. Remmele , H.-E. Stegner

Breast cancer and hormone-replacement therapy in the Million Women Study

2003-08-01

Valerie Beral

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The Protective Effects of Estrogen on the Cardiovascular System

1999-06-10

Michael E. Mendelsohn , Richard H. Karas

The incidence of cardiovascular disease differs significantly between men and women, in part because of differences in risk factors and hormones.1 The incidence of atherosclerotic diseases is low in premenopausal … The incidence of cardiovascular disease differs significantly between men and women, in part because of differences in risk factors and hormones.1 The incidence of atherosclerotic diseases is low in premenopausal women, rises in postmenopausal women, and is reduced to premenopausal levels in postmenopausal women who receive estrogen therapy.13 Until recently, the atheroprotective effects of estrogen were attributed principally to the hormone's effects on serum lipid concentrations. However, estrogen-induced alterations in serum lipids account for only approximately one third of the observed clinical benefits of estrogen.35 Reviews of the data suggest that the direct actions of estrogen on blood . . .

Differential Ligand Activation of Estrogen Receptors ERα and ERβ at AP1 Sites

1997-09-05

Kolja Paech , Paul Webb , George G. J. M. Kuiper +4 more

The transactivation properties of the two estrogen receptors, ERα and ERβ, were examined with different ligands in the context of an estrogen response element and an AP1 element. ERα and … The transactivation properties of the two estrogen receptors, ERα and ERβ, were examined with different ligands in the context of an estrogen response element and an AP1 element. ERα and ERβ were shown to signal in opposite ways when complexed with the natural hormone estradiol from an AP1 site: with ERα, 17β-estradiol activated transcription, whereas with ERβ, 17β-estradiol inhibited transcription. Moreover, the antiestrogens tamoxifen, raloxifene, and Imperial Chemical Industries 164384 were potent transcriptional activators with ERβ at an AP1 site. Thus, the two ERs signal in different ways depending on ligand and response element. This suggests that ERα and ERβ may play different roles in gene regulation.

Differential oestrogen receptor binding is associated with clinical outcome in breast cancer

2012-01-01

Caryn S. Ross-Innes , Rory Stark , Andrew E. Teschendorff +7 more

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Correction: Loss of CDYL results in suppression of CTNNB1 and decreased endometrial receptivity

2025-06-25

Xiaowei Zhou , Bufang Xu , Dan Zhang +5 more | Frontiers in Cell and Developmental Biology

Anti-Neoplastic Activity of Estrogen Receptor Beta in Chemoresistant Triple-Negative Breast Cancer

2025-06-25

Xiyin Wang , Michael J. Emch , Matthew P. Goetz +1 more | Cancers

Background: Targeted therapies, such as endocrine agents, have significantly improved outcomes for patients with estrogen receptor alpha-positive (ERα+) breast cancer. Unfortunately, for patients with triple-negative breast cancer (TNBC), which lack … Background: Targeted therapies, such as endocrine agents, have significantly improved outcomes for patients with estrogen receptor alpha-positive (ERα+) breast cancer. Unfortunately, for patients with triple-negative breast cancer (TNBC), which lack expression of ERα and HER2, there remains a dearth of targeted adjuvant agents. We discovered that estrogen receptor beta (ERβ) is expressed in approximately 20% of TNBC cases, and its activation has been shown to inhibit proliferation, invasion, and migration in preclinical models. However, it remains unclear whether ERβ-targeted therapies maintain efficacy following the development of chemoresistance. Methods: To address this question, we generated ERβ+ TNBC cell line models with acquired resistance to paclitaxel or doxorubicin. We then assessed their response to ERβ-targeted therapies and analyzed transcriptomic changes associated with chemoresistance and ERβ ligand treatment. Results: Chemotherapy-resistant ERβ+ TNBC cells retained sensitivity to ERβ-targeted therapies and, in some cases, exhibited enhanced responsiveness. ERβ expression did not compromise chemotherapy efficacy in treatment-naïve cells. Chemotherapy-resistant cells had a vastly altered transcriptome and surprisingly, a heavily reduced ERβ transcriptome, compared to sensitive cells despite the maintenance of ERβ-driven anti-neoplastic activity. Conclusions: These findings suggest that ERβ remains a relevant drug target in chemotherapy-refractory disease and has aided in the refinement of a minimal ERβ transcriptomic signature associated with response to ERβ-targeting agents, further informing the primary mechanisms through which ERβ elicits its tumor suppressive effects.

c-MYC Levels and Metabolic Parameters in Triple-Positive and Triple-Negative Breast Cancer

2025-06-25

Doaa N. Abood , Perry H. Saifallah | Diyala Journal of Medicine

Background: Breast cancer is a complex, heterogeneous disease and the most common malignancy among women. It is classified based on the presence of estrogen receptors (ER), progesterone receptors (PR), and … Background: Breast cancer is a complex, heterogeneous disease and the most common malignancy among women. It is classified based on the presence of estrogen receptors (ER), progesterone receptors (PR), and HER2. Rapid proliferation of cancer cells increases their energy demands leading to enhanced glycolysis and lactate accumulation. Lactate dehydrogenase (LDH) is pivotal in this process, particularly in tumors with anaerobic metabolism. The transcription factor c-Myc (cellular myelocytomatosis oncogene) promotes aerobic glycolysis by increasing glucose uptake and lactate production are a hallmark of the Warburg effect. Objectives: This study was aimed to evaluate c-Myc expression levels in patients with triple-positive breast cancer (TPBC) and triple-negative breast cancer (TNBC), comparing them to healthy control. Patients and Methods: The study included 80 women (ages 35–66): 20 with TNBC, 20 with TPBC, and 40 individual healthy as a control, matched for age, sex, and Body Mass Index (BMI). Serum levels of c-Myc, CA 27-29 was measured using an ELISA sandwich technique. Additionally, lactate dehydrogenase (LDH), glycated hemoglobin (HbA1c), liver enzymes (ALT and AST), and lipid profiles were assessed using spectrophotometric techniques. Results: c-Myc levels were significantly higher in breast cancer patients (4.71 ± 3.75 ng/ml) compared to controls (0.81 ± 0.44 ng/ml, p = 0.001). LDH and CA 27-29 levels were significantly elevated (p = 0.001). Metabolic parameters, including HbA1c%, ALT, AST, and lipid profiles (except HDL), showed significant changes, with reduced HDL levels in cancer patients. Notably, TNBC patients exhibited higher c-MYC and HbA1c levels compared to TPBC patients. Conclusion: Elevated c-Myc levels are associated with metabolic reprogramming in breast cancer and may serve as a potential therapeutic target. The higher c-Myc expression in TNBC correlates with its more aggressive nature, suggesting c-Myc's role in tumor progression. Keywords: Breast cancer, c-Myc, Lactate dehydrogenase, Triple-negative breast cancers, Triple-positive breast cancer.

Association between CYP17A1 rs743572 polymorphism and cancer risk: A meta-analysis

2025-06-25

Bin Wang , Zhijun Cao , Yinghong Li +1 more | PLoS ONE

The role of the CYP17A1 gene’s rs743572 polymorphism in cancer susceptibility has been a subject of extensive investigation, yet existing evidence remains inconclusive. In this meta-analysis, we systematically reviewed and … The role of the CYP17A1 gene’s rs743572 polymorphism in cancer susceptibility has been a subject of extensive investigation, yet existing evidence remains inconclusive. In this meta-analysis, we systematically reviewed and synthesized data from 29 studies to assess the CYP17A1 rs743572 polymorphism’s relationship with cancer susceptibility. We strictly searched on EMBASE, PubMed, and Web of Science databases and explored rs743572 polymorphism’s association with cancer risks according to search strategy, enrolling 29 studies (13,767 cases and 17,441 controls). rs743572 was markedly related to enhanced cancer susceptibility risk; FPRP and TSA analyses were employed for confirmation. According to cancer type-based stratified analyses, rs743572 exhibited a notable association with bladder cancer, breast cancer, non-Hodgkin lymphoma, and hepatocellular cancer. In conclusion, systematic meta-analysis suggests a significant role for the rs743572 polymorphism in cancer pathogenesis, with particular prominence observed in bladder cancer, breast cancer, non-Hodgkin lymphoma, and hepatocellular cancer.

Disposition and Absolute Bioavailability of Oral Imlunestrant in Healthy Women: A Phase 1, Open‐Label Study

2025-06-24

Amita Datta‐Mannan , Boris A. Czeskis , Elaine Shanks +4 more | Clinical Pharmacology in Drug Development

Abstract Imlunestrant (LY3484356) is a next‐generation orally bioavailable selective estrogen receptor degrader being investigated for the treatment of estrogen receptor–positive advanced breast and endometrial cancers. This Phase 1, open‐label, 2‐part … Abstract Imlunestrant (LY3484356) is a next‐generation orally bioavailable selective estrogen receptor degrader being investigated for the treatment of estrogen receptor–positive advanced breast and endometrial cancers. This Phase 1, open‐label, 2‐part study evaluated the disposition and absolute bioavailability of [ 14 C]‐imlunestrant in 16 US‐based healthy women (aged 36‐65 years) of non–childbearing potential. Part 1 participants (N = 8) received an oral dose of 400‐mg [ 14 C]‐imlunestrant solution (100 µCi). Part 2 participants (N = 8) received an oral dose of 2 × 200‐mg imlunestrant tablets followed by approximately 45 µg [ 14 C]‐imlunestrant (approximately 1 µCi) given as a 15‐minutes infusion 4 hour later. Blood, fecal, and urine samples were collected. Total radioactivity was primarily eliminated in feces (97.3%) with trace amounts recovered in urine (0.278%), suggesting minimal renal clearance. Imlunestrant accounted for most of the radioactive dose in feces (61.8%), followed by metabolite M2 (20.9%), metabolites M5 + M10 (coeluted), M7, M8, M9, and M11 (5.1% or less for each). Absolute bioavailability of imlunestrant after oral administration relative to intravenous administration was 10.9% based on dose‐normalized area under the concentration–time curve from time zero to infinite time. Imlunestrant was well tolerated as an oral solution or as a tablet/intravenous dose. Eight participants reported mild/moderate treatment‐related adverse events that resolved by the end of the study.

Anti-osteoporosis Activity of Sodium Glucuronate in Preosteo-blast MC3T3-E1 Cells and an Ovariectomized Rat Model

2025-06-24

Anqi Wang , Biyao Liu , Qingkai Zeng +7 more | Biological and Pharmaceutical Bulletin

The purpose of this study was to explore the potential therapeutic effect of sodium glucuronate (SG) on osteoporosis (OP). To achieve this aim, the optimal concentration of SG for stimulating … The purpose of this study was to explore the potential therapeutic effect of sodium glucuronate (SG) on osteoporosis (OP). To achieve this aim, the optimal concentration of SG for stimulating MC3T3-E1 osteoblast cells derived from the calvaria of neonatal mice was determined using cell counting kit-8 and alkaline phosphatase (ALP) activity assays. Osteogenic markers were analyzed by qRT-PCR and Western blotting. The histopathological morphology of the tibial tissues was performed using hematoxylin and eosin staining. The levels of bone turnover markers (BTMs) were assessed using enzyme-linked immunosorbent assay (ELISA). SG treatment was found to effectively promote osteoblastic differentiation and mineralization in MC3T3-E1 cells, evidenced by enhanced ALP activity, increased calcium deposition, and upregulated expression of key osteogenic markers including runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), and osteopontin (OPN). Moreover, in ovariectomized rats, a model of postmenopausal OP, SG treatment significantly promoted bone formation, regulated the levels of BTMs, and augmented bone mineral density. Consistently, SG upregulated the expression of osteogenic genes (RUNX2, OCN, and OPN) in bone tissue, further supporting its osteogenic potential. Collectively, these findings suggest that SG possesses the ability to stimulate bone formation and may hold promise as a potential agent for the management of OP.

The dual role of GPX4 in breast cancer: mechanisms of therapeutic resistance and potential for novel targeted therapies

2025-06-24

Tingyu Gu , Kun Wang , Xiao Yuan +3 more | Cancer Gene Therapy

Expression Dynamics and Estrogen Response of Estrogen Receptors in Duolang Sheep During Puberty

2025-06-24

Lihui Zhu , Gul Muhammad Shahbaz , Huiping Sun +4 more | Genes

Background/Objectives: Puberty is a critical stage in sheep development when reproductive capability is established, but the hormonal mechanisms underlying this transition remain incompletely understood. This study aimed to investigate the … Background/Objectives: Puberty is a critical stage in sheep development when reproductive capability is established, but the hormonal mechanisms underlying this transition remain incompletely understood. This study aimed to investigate the dynamic changes in estradiol (E2) levels and the expression patterns of estrogen receptors (ERα and ERβ) during puberty in Duolang sheep, a breed characterized by early sexual maturity and high reproductive efficiency. Methods: A total of 18 female Duolang sheep were assigned to three developmental stages (n = 6 per group): prepuberty (145 days), puberty (within 0 h of first estrus), and postpuberty (+3 days). Serum E2 concentrations and the mRNA and protein levels of ERα and ERβ were assessed in the hypothalamus, pituitary, and ovary. Additionally, primary ovarian granulosa cells (GCs) were isolated and stimulated in vitro with increasing concentrations of E2 (0–1000 ng/mL) to evaluate the dose-dependent expression of ERα, ERβ, and gonadotropin-releasing hormone (GnRH). Results: E2 levels peaked at the onset of puberty and declined thereafter. ERα expression in the hypothalamus and pituitary decreased during puberty but rebounded postpuberty, indicating a role in negative feedback regulation. In contrast, ovarian ERα expression reached its highest level during puberty, while ERβ expression in the ovary gradually increased from prepuberty to postpuberty. In GCs, ERα exhibited a biphasic expression pattern, peaking at 250 ng/mL E2 and decreasing at higher concentrations. ERβ and GnRH expression levels increased in a dose-dependent manner. Conclusions: These findings suggest that ERα primarily mediates E2 feedback within the hypothalamus–pituitary axis, whereas ERβ is associated with ovarian development and may regulate GnRH expression during the pubertal transition. The study provides new insights into the hormonal regulation of puberty in Duolang sheep and offers potential biomarkers for improving reproductive efficiency through targeted breeding strategies.

Metabolic Messengers: oestradiol

2025-06-24

Andrea L. Hevener , Stephanie M. Correa | Nature Metabolism

Systemic glucocorticoids and the risk of breast cancer in a large nationwide case–control study

2025-06-23

Manon Cairat , Morten Olesen , Elea Olivier +2 more | Breast Cancer Research

The role of estrogen receptor β in maintaining basal cells and modulating the immune environment in the prostate

2025-06-23

Wanfu Wu , Xiao-Yu Song , Margaret Warner +3 more | Proceedings of the National Academy of Sciences

Estrogen receptor β (ERβ) plays an important role in both the mouse and human prostate. The endogenous ligand for ERβ is the dihydrotestosterone metabolite, 5β-androstane-3β, 17β-diol (3β-Adiol). Thus, treatment with … Estrogen receptor β (ERβ) plays an important role in both the mouse and human prostate. The endogenous ligand for ERβ is the dihydrotestosterone metabolite, 5β-androstane-3β, 17β-diol (3β-Adiol). Thus, treatment with 5-α reductase inhibitor (5-ARI) should produce a phenotype similar to that seen in ERβ-/- mice. By comparing RNA-Seq of the ventral prostates (VP) of ERβ knockout mice (ERβcrispr-/-) and wild-type (WT) mice, we confirmed that ERβ modulates androgen receptor (AR) signaling indirectly by suppressing AR coactivators. Compared to WT mice, basal cell genes from ERβcrispr-/- mouse VP were significantly upregulated. A population of abnormal basal cells coexpressing P63 and AR was identified in the ERβcrispr-/- mouse VP by immunohistochemistry. In men treated with 5-ARI for treatment of benign prostatic hyperplasia (BPH), there was induction of a P63-positive intermediate cell population characterized by down regulation of Krt14 without significant change in the expression of Krt15, upregulation of AR and NKX3.1, and increased proliferation. In both VP of aging ERβcrispr-/- mice and in human prostates after 5-ARI treatment, there was substantial immune infiltration. Testosterone treatment inhibited immune infiltration in the VP of ERβcrispr-/- mice. We conclude that ERβ is a gene critical in maintaining normal basal cells and modulating immune environment in the prostate. Its loss leads to histological changes suggesting prostatitis and increases the number of intermediate cells, which are considered to be the cells of origin of prostate cancers. We suggest that an ERβ agonist could protect against 5-ARI-induced inflammatory cell infiltration and defects in the basal cell layer in BPH.

Anti-Inflammatory Peptide Prevents Aβ25–35-Induced Inflammation in Rats via Lipoxygenase Inhibition

2025-06-23

Yad Ram Yadav , Masroor Anwar , Hanuman Prasad Sharma +5 more | Cells

Neuroinflammation, triggered by lipoxygenase (LOX), contributes to Alzheimer’s disease (AD) progression. Overexpression of LOX-5 in patients with AD serum highlights its role. This study assessed the efficacy of the LOX-inhibitor-peptide … Neuroinflammation, triggered by lipoxygenase (LOX), contributes to Alzheimer’s disease (AD) progression. Overexpression of LOX-5 in patients with AD serum highlights its role. This study assessed the efficacy of the LOX-inhibitor-peptide YWCS in an AD rat model induced by Aβ25–35 injection. Cognitive tests, magnetic resonance imaging (MRI) scans, and molecular analyses were conducted. YWCS treatment significantly improved cognitive function, as evidenced by improved performance in the open field, novel object recognition, elevated plus maze, and Morris water maze tests. MRI scans revealed hippocampal shrinkage in AD rats and no changes were observed from YWCS treatment. Molecular analysis revealed altered expression of LOX-5, LOX-12, Aβ, γ-secretase components, p-Tau181, Akt, p-Akt, and p53 in AD rats. Immunofluorescence staining confirmed increased expression of LOX, Aβ, and p-Tau181 in the hippocampus of AD rats, which was reduced by YWCS treatment. Serum LOX levels were elevated in AD rats and significantly decreased after YWCS treatment, aligning with previous findings in human AD patients and AD cell models. YWCS offered improvements in behavioral and inflammatory marker regulation and also prevented progression of the disease, as shown by MRI results. These results suggest that YWCS, by targeting LOX, has the potential to be a promising therapeutic agent for AD.

Establishment and Characterization of a Durable and Versatile Endometrial Cancer Organoid Database

2025-06-22

Yifen Li , Gangwei Wang , Jianwei Chen +4 more | Indian Journal of Gynecologic Oncology

Abstract Objective To construct standardized endometrial cancer organoids. Method Preparation and culture of endometrial carcinoma organoids from human endometrial carcinoma tissues. Verified the consistency between organoids and primary carcinoma tissues … Abstract Objective To construct standardized endometrial cancer organoids. Method Preparation and culture of endometrial carcinoma organoids from human endometrial carcinoma tissues. Verified the consistency between organoids and primary carcinoma tissues through microscopic cell appearance and immunohistochemistry. Result The appearance and biomarkers of the constructed endometrial carcinoma organoid were consistent with those endometrial carcinoma cells from patients. Conclusion The appearance and biomarkers of the endometrial carcinoma organoid were consistent with those endometrial carcinoma cells from patients.

Adjuvant treatment with tamoxifen for estrogen receptor-positive breast cancer and gynecological risks in premenopausal and perimenopausal women – a systematic review

2025-06-20

Julie Isabelle Plougmann Gislinge , Kresten Rubeck Petersen , Signe Borgquist +1 more | Climacteric

Tamoxifen (TMX) is known to increase the risk of endometrial cancer (EC) in postmenopausal women, but data on the effects in premenopausal and perimenopausal women remain inconsistent and not well … Tamoxifen (TMX) is known to increase the risk of endometrial cancer (EC) in postmenopausal women, but data on the effects in premenopausal and perimenopausal women remain inconsistent and not well illuminated. This study aimed to evaluate whether TMX increases the risks of gynecological symptoms and EC in premenopausal and perimenopausal women receiving adjuvant therapy for estrogen receptor-positive breast cancer. Systematic searches in PubMed, Cochrane and Web Of Science yielded 319 relevant articles, of which 38 were analyzed after excluding duplicates and non-qualifying studies. The Oxford Criteria were used to ensure consistent evaluation before final inclusion. No meta-analysis was conducted due to study heterogeneity. Ten studies (two meta-analyses, one systematic review, four retrospective cohort studies, one retrospective comparative study, one prospective cohort study and one case-control study) were included. TMX was associated with an increased risk of EC in premenopausal and perimenopausal women (mean relative risk 2.25; standard deviation 0.9) compared to no treatment or treatment with raloxifene or aromatase inhibitors. Risk appeared in some studies to increase with treatment duration and persisted for ≥5 years post treatment. TMX also significantly increased the risk of gynecological symptoms, benign and premalignant endometrial pathology, intrauterine procedures and hysterectomy (p < 0.001). TMX seems to increase EC risk and significantly increase the risk of gynecological symptoms in premenopausal and perimenopausal women, with risk persisting years following treatment cessation. Healthcare professionals should counsel these women on potential risks and emphasize prompt evaluation of gynecological symptoms.

GPER a Potent Target of Xenoestrogens: An Overview on Biological Activity and Mechanism of Action in Cancer and Immunogenic Pathway

2025-06-19

Sumana Das , Sudipta Majumdar nee Paul | Proceedings of the Zoological Society

The oestrogen equation: What is the key to unlocking the cardiovascular benefits of oestrogen for postmenopausal women?

2025-06-19

Allyson I. Schwab , Virgina R. Nuckols , Emily Shaw +2 more | The Journal of Physiology

Structural evolution progress of orally bioavailable selective estrogen receptor degraders

2025-06-19

Jiahe Zhang , Jiachen Zhang , Ying Zhao +4 more | Bioorganic & Medicinal Chemistry

Omega-3 fatty acids improves tamoxifen-induced sexual dysfunction in male Wistar rats by modulating NO/cGMP signaling and monoamine neurotransmitters activities

2025-06-18

Adeyemi Fatai Odetayo , Roland Eghoghosoa Akhigbe , Moses Agbomhere Hamed +3 more | Psychopharmacology

Correlation of Serum sIL-2R, VEGF, and ES with Estrogen Levels in Papillary Thyroid Carcinoma Patients and Their Predictive Value for Postoperative Recurrence

2025-06-17

Yan Guo , Xin Ci , Simon X. Han +1 more | Journal of Medical Biochemistry

Objective: To explore the correlation of serum soluble interleukin-2 receptor (sIL-2R), vascular endothelial growth factor (VEGF), and endostatin (ES) with estrogen levels in papillary thyroid carcinoma (PTC) patients, and to … Objective: To explore the correlation of serum soluble interleukin-2 receptor (sIL-2R), vascular endothelial growth factor (VEGF), and endostatin (ES) with estrogen levels in papillary thyroid carcinoma (PTC) patients, and to assess the predictive efficacy of these biomarkers for PTC diagnosis and postoperative recurrence. Methods: From March 2023 to March 2024, 132 newly diagnosed PTC patients and 128 healthy controls were enrolled. Serum sIL-2R, VEGF, and ES levels were quantified using enzyme-linked immunosorbent assay (ELISA), while estrogen levels (estrone [E1], estradiol [E2], estriol [E3]) were measured via chemiluminescent immunoassay. Patients were followed postoperatively for one year to monitor recurrence events, including local recurrence, lymph node metastasis, and distant metastasis. The diagnostic performance of the combined model was evaluated using receiver operating characteristic (ROC) curve analysis, and Pearson correlation analysis was conducted to examine the relationship between biomarkers and estrogen levels. Results: Compared to controls, PTC patients exhibited significantly elevated serum sIL-2R, VEGF, and ES levels (P<0.05). The combined detection of these biomarkers demonstrated a sensitivity of 80.30% and specificity of 78.91% (AUC=0.8526) for PTC diagnosis. Additionally, E1 and E2 levels were significantly higher in PTC patients (P<0.05) and showed positive correlations with sIL-2R, VEGF, and ES (P<0.05), whereas E3 levels changed insignificantly (P>0.05). Recurrent patients had significantly higher sIL-2R, VEGF, and ES levels than non-recurrent patients (P<0.05). The combined predictive model for recurrence achieved a sensitivity of 96.88% and specificity of 61.00% (AUC=0.8494). Conclusion: Elevated serum sIL-2R, VEGF, and ES levels in PTC patients indicate that their combined assessment may serve as a sensitive and specific tool for PTC diagnosis and postoperative recurrence risk stratification.

Menin inhibitors from monotherapies to combination therapies: clinical trial updates from 2024 ASH annual meeting

2025-06-17

Guangwen Cao , Haixiao Zhang , Shu Sun +1 more | Journal of Hematology & Oncology

Membrane-initiated estrogen receptor-α signaling in osteoblasts is crucial for normal regulation of the cortical bone in female mice

2025-06-17

Yiwen Jiang , Karin Horkeby , Petra Henning +7 more | Bone Research

The gene regulatory effects of selective glucocorticoid receptor ligands

2025-06-16

Nicholas S. Giroux , Graham D. Johnson , Alejandro Barrera +1 more | bioRxiv (Cold Spring Harbor Laboratory)

Synthetic glucocorticoids (GCs), which induce the transcription factor activity of the glucocorticoid receptor (GR), are frequently prescribed anti-inflammatory therapeutics that have been in use for over 70 years. Despite their … Synthetic glucocorticoids (GCs), which induce the transcription factor activity of the glucocorticoid receptor (GR), are frequently prescribed anti-inflammatory therapeutics that have been in use for over 70 years. Despite their broad immunosuppressive utility, sustained use of GCs is often intolerable due to the prevalence of adverse side effects. A longstanding goal has been to make synthetic GCs safer by developing selective GR ligands that have similar anti-inflammatory activity but without the burden of side effects. To evaluate the ability of synthetic GCs to target specific subsets of the GC response, we completed a genome-wide comparative analysis of changes in gene expression and gene regulatory element activity in response to ten ligands with various evidence of dissociated adverse side effects. We measured the gene expression response using mRNA-seq and the gene regulatory element response using genome-wide STARR-seq. Effects associated with each ligand were highly correlated with and linearly related to the response to dexamethasone, a strong, non-selective GR agonist used as a positive control for this study. Furthermore, 93% of the variation in regulatory element activity responses could be explained by the efficacy of each ligand alone. We also found limited evidence of differential enrichment of chromatin context-specific markers of regulatory activity with each ligand. Based on those findings, we developed a simulation framework to evaluate selectivity of GR ligands. We conclude that the ligands we tested elicit attenuated molecular responses according to their respective efficacies, and do not selectively target subsets of the molecular GC response.

Discovery of Diaryl Piperidone-Sulfonamide as a Novel Dual-Target Inhibitor of STAT3/CAIX Inducing Ferroptosis in Triple-Negative Breast Cancer Cells

2025-06-14

Lei Chen , Xiao-Man Chen , Zhi-Chen Mao +5 more | Journal of Medicinal Chemistry

A series of diaryl piperidone-sulfonamide derivatives were designed as dual inhibitors of STAT3/CAIX and ferroptosis inducers for triple-negative breast cancer (TNBC). The representative compound 7m demonstrated significant antitumor effects against … A series of diaryl piperidone-sulfonamide derivatives were designed as dual inhibitors of STAT3/CAIX and ferroptosis inducers for triple-negative breast cancer (TNBC). The representative compound 7m demonstrated significant antitumor effects against the MDA-MB-231 cell line both in vitro and in vivo. Mechanistically, 7m inhibits the phosphorylation of STAT3, with a binding affinity determined by surface plasmon resonance (SPR) analysis (KD = 60.03 ± 8.13 μM). Additionally, 7m exhibits potent inhibitory activity against CA IX (IC50 = 80.45 ± 39.7 nM) and shows enhanced antitumor activity under hypoxic conditions compared to normoxic conditions. Molecular docking studies suggest a rational binding mode between 7m and the SH2 domain of STAT3, as well as with the CA IX protein. Furthermore, 7m increases the levels of reactive oxygen species (ROS) and lipid peroxides in MDA-MB-231 cells, thereby inducing ferroptosis. These findings provide a novel therapeutic strategy for the treatment of TNBC.

Chromatin insulators: Good fences that make good neighbors

2025-06-14

Laura Arribas‐Hernández | The Plant Cell

Synthesis of 20-hydroxyprogesterone-trimethyl lock-triglyceride-mimetic prodrugs and its bioavailability study in rats

2025-06-14

Liang‐yun Li , Shujing Yan , Yuexuan Cheng +5 more | Bioorganic & Medicinal Chemistry

In-silico identification of novel inhibitors of human androgen receptors and prostrate-specific membrane antigen: a comprehensive target-based molecular docking, molecular dynamics simulation, and ADME-toxicity studies

2025-06-13

Adejoke Oluwaseun Osideko , Ibrahim Olaide Adedotun , Misbaudeen Abdul-Hammed +1 more | In Silico Pharmacology

Abstract P5-06-28: Characterization of cell type specific distal cis-regulatory elements from 5’ scRNA-seq in estrogen receptor positive breast cancer patients treated with aromatase inhibitors

2025-06-13

Villads Winton , Ilayda Altinönder , Marie Fongaard +7 more | Clinical Cancer Research

Abstract Introduction: Aromatase inhibitors (AIs) are widely used in the treatment of estrogen receptor-positive (ER+) breast cancer to inhibit estrogen production and suppress the ER signaling pathway. Target genes regulated … Abstract Introduction: Aromatase inhibitors (AIs) are widely used in the treatment of estrogen receptor-positive (ER+) breast cancer to inhibit estrogen production and suppress the ER signaling pathway. Target genes regulated by estrogen stimulation of ER+ malignant cells lead to uncontrolled proliferation. The NEOLETEXE trial evaluated the sequential use of letrozole (2.5 mg daily) and exemestane (25 mg daily) in the neoadjuvant setting. We performed single-cell RNA sequencing (scRNA-seq) on 24 patients enrolled in the NEOLETEXE trial (i) before treatment, (ii) before change of AI (crossover at 3 months), and (iii) at the end of neoadjuvant therapy (6 months of treatment). Methods and aims: We aim at characterizing the distal and proximal regulatory elements in different cell types and states observed in longitudinally collected tumor samples. Transcription factor regulatory networks are important determinants of ER+ breast cancer pathogenesis. Understanding the dynamic changes in regulatory element usage under treatment pressure will help to map the molecular events associated with sensitivity or resistance to AI therapy. We used SCAFE (Single-Cell Analysis of Five-prime Ends), a computational method that maps transcribed cis-regulatory elements (CREs) in single cells using 5’ end scRNA-seq data. Results: Using unsupervised clustering of scRNA gene expression, we identified the major cell types in ER+ breast tumors. SCAFE was applied to identify 99,996 distal CREs (i.e., enhancers) in a cell type-agnostic manner. We quantified the reads mapping to each distal CRE in each cell creating a cell-by-distal CRE count matrix. We employed a Latent Dirichlet Allocation topic model implemented in pyCistopic to evaluate the significance of enhancers in determining cell phenotypes. Additionally, we characterized the distal CRE landscape specific to each cell type and state, providing an atlas of cell type-specific enhancer usage in breast tumors. By predicting direct transcription factor binding to the corresponding CRE’s DNA sequences using UniBind, we identified ESR1, FOXA1, and GATA3 as transcription factors associated with enhancers in malignant cells. In contrast, in immune cells such as T cells, we found enriched binding sites for RUNX1, ETS, and TBX21. Conclusions: Using 5' end scRNA-seq data, we successfully generated an atlas of distal regulatory elements for each cell in breast tumors. We identified the transcription factors likely to activate these cell type-specific distal regulatory elements. Mapping distal regulatory elements usage and transcriptomes in single cells allows us to study the interplay between enhancer activity, transcription factor binding, and gene regulation. It provides insights into the molecular mechanisms of AI therapy sensitivity and resistance and sheds light on the driver pathways associated with cell phenotypes and states in ER+ breast cancer. Citation Format: Villads Winton, Ilayda Altinönder, Marie Fongaard, Pål Marius Bjørnstad, Knut Selsås, Stephanie Beate Geisler, Manouchehr Seyedzadeh, Unn-Cathrin Buvarp, Torben Lüders, Marianne Lyngra, Arnoldo Frigessi, Vessela Kristensen, Anthony Mathelier, Jürgen Geisler, Xavier Tekpli. Characterization of cell type specific distal cis-regulatory elements from 5’ scRNA-seq in estrogen receptor positive breast cancer patients treated with aromatase inhibitors [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-06-28.

Abstract P5-09-23: Programmed death-ligand 1 expression in a Mexican cohort of triple-negative breast cancer

2025-06-13

Alejandro Aranda-Gutierrez , Cynthia Villarreal‐Garza , César Octavio Lara-Torres +7 more | Clinical Cancer Research

Abstract Programmed death-ligand 1 (PD-L1) expression predicts response to immunotherapy in a range of malignancies, including triple-negative breast cancer (TNBC). However, observational studies show a significant variability in the rates … Abstract Programmed death-ligand 1 (PD-L1) expression predicts response to immunotherapy in a range of malignancies, including triple-negative breast cancer (TNBC). However, observational studies show a significant variability in the rates of PD-L1 positivity in TNBC. Currently, PD-L1 expression rates remains unknown in the Mexican population. A retrospective multicenter study of women with newly diagnosed TNBC between 2006 and 2021 was carried out. PD-L1 was assessed at a central laboratory using the IHC 22C3 assay. Expression was characterized according to the combined positive score (CPS), with positivity defined as &gt;1%. Descriptive statistics were employed to calculate means, percentages, and standard deviations. Among 298 cases with available tissue for analysis, 285 (96%) samples had sufficient cellularity for adequate CPS evaluation. In the entire cohort, the PD-L1 positivity rate was 29.1%, while 13.3% had a CPS &gt;10%. The prevalence of PD-L1 positivity differed significantly according to histological grade, percentage of tumor-infiltrating lymphocytes, and the tissue type analyzed. The majority of CPS evaluations were performed on tissue from biopsies of the primary tumor, which can underestimate PD-L1 positivity by 20-30% when compared to matched surgical specimens. Furthermore, biopsies from metastatic sites were not analyzed for PD-L1 expression, which can impact overall CPS positivity rates. Our data underscore the importance of considering the source of the tissue sample when interpreting PD-L1, as different types and sites of biopsy may yield different expressions. Citation Format: Alejandro Aranda-Gutierrez, Cynthia Villarreal-Garza, César Octavio Lara-Torres, J. Edgardo Hernandez, Daniela Vázquez Juárez, Gabriela Sofía Gómez-Macías, Alejandro Aranda-Gutierrez, Paula Anel Cabrera-Galeana, Fany Iris Porras-Reyes, Víctor Manuel Pérez-Sánchez, Antonio Nateras-Pérez, Alejandro Mohar. Programmed death-ligand 1 expression in a Mexican cohort of triple-negative breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-09-23.

Abstract P2-06-03: Age Conditions the Tumor Microenvironment of Hormone Receptor Positive Breast Cancer

2025-06-13

Mackenzie L. Hawes , Megan C. Benz , Sophie R. Dietrich +6 more | Clinical Cancer Research

Abstract Hormone receptor positive (HR+) breast cancer is the predominant molecular subtype in postmenopausal women. Although menopause decreases the concentration of estrogen in the body, HR+ breast tumors are sustained … Abstract Hormone receptor positive (HR+) breast cancer is the predominant molecular subtype in postmenopausal women. Although menopause decreases the concentration of estrogen in the body, HR+ breast tumors are sustained by local production of estrogens in the surrounding adipose tissue. The aged breast is characterized by an expansion of white adipose tissue, a phenomenon with unknown implications for breast cancer progression and treatment. Current clinical trials focused on HR+ breast cancer treatment fail to accurately represent aged women, with the average age of enrollment 7.76 years younger than the average age at diagnosis. It is important to understand how age-related changes to this environment impact disease progression, as breast adipose tissue both surrounds and bidirectionally communicates with cancer cells. Considering that age is not accurately represented in clinical trials, there remains a critical need for clinically relevant models of aged HR+ tumors and breast adipose in vitro. This project set out to characterize how age-based differences in the microenvironment alter HR+ tumor growth and disease progression, using a combination of in vivo analyses of age and in vitro conditioned media studies. Our results show that tumors from aged mice have a higher growth rate and overall total tumor volume at endpoint compared to young counterparts, indicating age as a driver in vivo tumorigenesis. In vitro proteomic analysis demonstrated that HR+ cancer cells exposed to conditioned media from aged breast adipose derived stem cells (brASC) have elevated expression of markers associated with adhesion, EMT, and angiogenesis at the mRNA and protein levels. Cytokine arrays of aged tumors show decreased expression of CXCL12/SDF1 and increased expression of SERPINE1, supporting possible changes in adhesion, EMT, and extracellular matrix with age. These findings suggest that age-educated components of the tumor microenvironment alter signaling within the tumor and promote tumorigenesis. Citation Format: Mackenzie Hawes, Megan C. Benz, Sophie R. Dietrich, Jack D. North, Bruce A. Bunnell, Bridgette M. Collins-Burow, Van T. Hoang, Elizabeth C. Martin, Matthew E. Burow. Age Conditions the Tumor Microenvironment of Hormone Receptor Positive Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-06-03.

Abstract P2-04-03: Progesterone Receptor-Stimulated MicroRNAs Regulate Breast Cancer Proliferation

2025-06-13

Motoki Takaku , Annika Price , Jonathan M. Goodman +1 more | Clinical Cancer Research

Abstract Background: Breast cancer development is closely linked to the activity of hormone receptors, including estrogen receptors (ER) and progesterone receptors (PR). While the role of ER in breast cancer … Abstract Background: Breast cancer development is closely linked to the activity of hormone receptors, including estrogen receptors (ER) and progesterone receptors (PR). While the role of ER in breast cancer and its targeted therapies are well-understood and established in clinical practice, the function of PR remains underexplored. This is despite its presence in approximately 70% of breast cancers and the promising inhibitory effects of progesterone treatment. This knowledge gap, along with the dual role of progesterone in both promoting and inhibiting breast cancer, underscores the urgent need for more detailed investigations into PR mechanisms. Methods: We conducted a microRNA (miRNA) expression analysis and identified 41 differentially expressed miRNAs upon progesterone stimulation. Many upregulated miRNAs are predicted to target cell cycle regulatory genes, suggesting that PR may regulate breast cancer proliferation through miRNAs. Consequently, we employed a CRISPR knockout screening to explore the roles of these progesterone-stimulated miRNAs. In this screening, T47D luminal breast cancer cells were treated with progesterone for one month, and resistant clones were isolated for downstream analysis. Results: The CRISPR screening indicated enrichment of gRNAs targeting four miRNAs post-progesterone exposure. PR binding was observed near these miRNAs, suggesting direct regulation by PR. The depletion of these miRNAs in T47D cells led to resistance to progesterone treatment. Notably, among these, the expression of miR-30a correlates with PR expression and patient prognosis in breast cancer clinical data. Conclusion: This study identifies PR-stimulated miRNAs that are crucial for inhibiting growth in luminal breast cancer cells. These findings shed light on how progesterone-activated PR may inhibit tumor growth in breast cancer, providing new insights for potential therapeutic targets. Citation Format: Motoki Takaku, Annika Price, Jill Goodman, Edward Looker. Progesterone Receptor-Stimulated MicroRNAs Regulate Breast Cancer Proliferation [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-04-03.

Abstract P4-05-22: Discovery of Molecules Synergistic with (Z)-endoxifen for the Treatment of Breast Cancer

2025-06-13

Daniela Hühn , Maria Häggblad , Anastasia Shneyderman +7 more | Clinical Cancer Research

Abstract Background: (Z)-endoxifen is a potent selective estrogen receptor modulator (SERM) with 100-fold more potency than its parent drug, tamoxifen. It is hypothesized that (Z)-endoxifen has a dual concentration dependent … Abstract Background: (Z)-endoxifen is a potent selective estrogen receptor modulator (SERM) with 100-fold more potency than its parent drug, tamoxifen. It is hypothesized that (Z)-endoxifen has a dual concentration dependent mechanism of action. At lower concentrations, (Z)-endoxifen is an ER antagonist while at higher concentrations (Z)-endoxifen additionally inhibits and degrades protein kinase C beta 1 (PKCβ1). Preclinical and clinical studies in bipolar disease, ER+ breast cancer and other solid tumor types have demonstrated (Z)-endoxifen to be safe and well tolerated. Specifically, in ER+/HER2- breast cancer (Z)-endoxifen has shown promising anti-tumor activity (EVANGELINE; NCT05601004). The objective of this study was to evaluate the synergistic potential of (Z)-endoxifen by identifying new combination therapeutic solutions in breast cancer. Methods: Insilico modeling: The artificial intelligence-driven platform PandaOmics was used to collect and aggregate omics-based gene signatures of breast cancer and (Z)-endoxifen and combine these with over 3000 small molecule perturbations from the LINCS database to predict compounds that could be synergistic with (Z)-endoxifen. All possible combinations with (Z)-endoxifen were evaluated by several ranked scores which included effects on disease signature and direction of gene expression changes, applying a gene-gene synthetic lethality component. Thus, drug pairs with highest combined scores are predicted to be potentially synergistic. Chemical screen: A total of 5251 compounds from the Drug Repurposing Library (SPECS) were screened for synergy with (Z)-endoxifen. MCF-7 cells (ER+ breast cancer) were treated with 0.5µM (Z)-endoxifen, dispensed into 384-well plates and exposed to 1 μM of compounds diluted in DMSO. After 4 days, cells were fixed and stained with Hoechst to visualize nuclei. Cells were imaged via high throughput microscopy (INCell 2200 microscope) and nuclei count was analyzed using CellProfiler. Statistical and data analysis was done using KNIME Software. All values were normalized to DMSO, no (Z)-endoxifen condition. Compounds reducing the viability of cells more than (Z)-endoxifen alone (mean viability -3x StD), and showing higher viability than Doxorubicin (10µM) combined with (Z)-endoxifen (mean viability +3x StD), were considered as hits and subjected to validation screening. Results: Insilico modeling identified compounds with inhibitory mechanism of actions against mTOR/PI3K, tyrosine kinase, topoisomerase, HDAC and CDKs in combination with (Z)-endoxifen as potentially synergistic. To validate these results, a chemical screen was conducted in MCF-7 cells. Results from this screen yielded a total of 354 compounds with synergistic potential with (Z)-endoxifen’s mechanism of action. The top-ranking compounds in the screen have mechanisms of actions centering on inhibition of DNA topoisomerase, CDK, mTOR/PI3K, AKT and HDAC. Nineteen compounds showed antagonistic activity. Ongoing studies will validate the chemical screening hits in additional breast cancer in vitro and in vivo models. Conclusions: Based on two independent approaches, compounds used to inhibit DNA topoisomerase, CDK, mTOR/PI3K and AKT synergize with (Z)-endoxifen to induce cell death in MCF-7 cells when compared to either agent alone. Taken together, these data suggest that combination therapies with (Z)-endoxifen and agents targeting topoisomerase, CDK, mTOR/PI3K and AKT hold great therapeutic potential and should be further validated in additional model systems. Citation Format: Daniela Hühn, Maria Häggblad, Anastasia Shneyderman, Alexander Veviorskiy, Khadija Alawi, Mikhail Korzinkin, Alex Zhavoronkov, John R. Hawse, Oscar Fernandez-Capetillo, Sandra S. Hammer, H. Lawrence Remmel, Steven C. Quay. Discovery of Molecules Synergistic with (Z)-endoxifen for the Treatment of Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-05-22.

Abstract P3-02-15: Combined Therapy of Progesterone Receptor Antagonist and COX-2 Inhibitor Prevents BRCA1-Deficient Mammary Tumorigenesis in Mice: A Novel Synthetic Lethal Strategy for Breast Cancer Prevention

2025-06-13

Oukseub Lee , Priyam Patel , Minhua Wang +3 more | Clinical Cancer Research

Abstract Background: we previously demonstrated that high-dose ulipristal acetate (UPA), a progesterone receptor (PR) antagonist, prevented tumors in a BRCA1-deficient mouse model. For a clinically relevant translation, this study aimed … Abstract Background: we previously demonstrated that high-dose ulipristal acetate (UPA), a progesterone receptor (PR) antagonist, prevented tumors in a BRCA1-deficient mouse model. For a clinically relevant translation, this study aimed to test the efficacy of low-dose UPA (5mg) alone and in combination with celecoxib (400mg), a COX-2 inhibitor, in Ad-K8-Cre Brca1f22-24/f22-24; Trp53f2-10/f2-10; R26Y (BPY) mice. This model allows tracing of tumor initiating cells (TICs) which are BRCA1; p53-deficient cells (YFP+) from initiation through premalignant stages and in tumors. We hypothesized that combination therapy enhances low-dose UPA efficacy. Methods: 2-month-old female BPY mice received intraductal Ad-K8-Cre injections. 10 days later they were randomized into four groups (no-drug control, UPA, celecoxib, and combination; 12 mice/group), and monitored for tumor formation for 21-months. Treatments were incorporated into their diet (Inotiv inc.). Cancer preventive efficacy of drug treatment compared to the control was analyzed using the log-rank test (SAS v9.4) and survival analysis (R package). The coefficient of drug interaction (CDI) is calculated using tumor-free survival % endpoint. Premalignant glands from 1- and 5-month cohorts (3 to 4 mice/group/cohort) were analyzed using fluorescence-activated cell sorting (FACS) and RNA sequencing to identify drug-modulated genes and pathways (P adjusted &lt;0.05). Results: Combo-therapy (UPA + celecoxib) showed excellent tumor-preventive efficacy whereas monotherapy of each drug failed. At 16 months, tumor incidence was similar among monotherapy and control groups (55-58%), while the combination group showed 8% incidence (p=0.02; HR = 0.12, 95% CI = 0.03-0.55). At 21 months, tumor incidence was lowest in the combination group (33%), followed by UPA (64%), control (73%), and celecoxib (92%) (p=0.03; HR = 0.29, 95% CI = 0.09-0.93). Combo-therapy resulted in a 92% tumor-free survival rate at 500 days, significantly greater than the pure additive effect for monotherapy (36% [UPA] + 42% [celecoxib]), with a CDI of 0.06, indicating strong synergy (CDI &lt;1). FACS analysis revealed that combo- therapy blocked the expansion of TICs (EpCAM+ YFP+), unlike monotherapy. Bulk RNA-seq analysis of TICs from the 1-month cohort showed that combo-therapy significantly increased luminal marker expression (Esr1, Pgr) and suppressed Tnfsf11 (RANKL), basal markers, and EMT genes. Single-cell RNA-seq of the 5-month cohort showed that luminal progenitors become dominant in TICs and combo-therapy upregulated the nonsense-mediated mRNA decay (NMD) pathway across multiple cell types and downregulated cancer-associated pathways (Wnt/β-catenin, TNFα via NF-κB, PI3K/AKT/mTOR, ECM organization) in epithelial cells. Conclusions: The combo-therapy of UPA and celecoxib showed superior efficacy in preventing cancer in a BRCA1-deficient mouse model, demonstrating strong synergy. These findings provide novel insights into the biology underlying BRCA1-associated tumorigenesis and support the clinical potential of PR antagonists and anti-inflammatory agents as a novel synthetic lethal strategy for breast cancer prevention in high-risk women. Citation Format: Oukseub Lee, Priyam Patel, Minhua Wang, Takahiro Tsukioki, Ruohui Chen, Seema Khan. Combined Therapy of Progesterone Receptor Antagonist and COX-2 Inhibitor Prevents BRCA1-Deficient Mammary Tumorigenesis in Mice: A Novel Synthetic Lethal Strategy for Breast Cancer Prevention [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-02-15.

Abstract P3-03-30: Molecular landscape of breast cancer in pre- and postmenopausal women

2025-06-13

Sameer S. Udhane , Pawan Noel , Fadel Alyaqoub +6 more | Clinical Cancer Research

Abstract Background: Breast cancer (BC) in younger women is often more aggressive and diagnosed at a later stage. The choice of endocrine therapy (ET) for women with hormone-receptor positive (HR+) … Abstract Background: Breast cancer (BC) in younger women is often more aggressive and diagnosed at a later stage. The choice of endocrine therapy (ET) for women with hormone-receptor positive (HR+) BC varies based on whether she is premenopausal (preM) or postmenopausal (postM): tamoxifen is usually selected for preM women, while postM women receive aromatase inhibitors (AIs). Approximately 20-30% of advanced HR+ BCs will develop ET resistance and progress on first-line therapy. Whether at progression or in the advanced/metastatic setting, comprehensive genomic profiling (CGP) may provide subsequent-line treatment options, including molecularly matched therapies. Evidence suggesting preM women with HR+ tumors have poor persistence with ET underscores the importance of identifying targets for later-line therapy to improve clinical outcomes for these younger patients. This study investigates the difference in biomarker alterations in preM and postM BC.. Methods: A retrospective analysis of BC samples analyzed with the OncoExTra® assay, which identifies somatic mutations and gene fusions by whole exome DNA sequencing and whole transcriptome sequencing, was performed. Because menopausal status was not available, patients were classified as preM or postM based on age: patients aged ≤50 years were considered preM, and those &gt;50 years were considered postM. The frequency of alterations in preM and postM HR+ BC was determined separately for samples collected from primary and metastatic sites. Potential associations between alterations and subgroups were evaluated using Fisher’s Exact Test and the Benjamini-Hochberg False Discovery Rate procedure. Results: We analyzed 2,573 BC samples with non-missing age, including 772 (30.0%) samples from preM women and 1,801 (70.0%) samples from postM women. Most samples were HER+/HER2- (1,721 (66.9%)), with smaller proportions of HER2+ (369 (14.3%)), triple-negative BC (TNBC; 377 (14.7%)), and not otherwise specified (106 (4.1%)) samples. In HR+/HER2- BC, alterations in several genes were more frequent in preM compared to postM samples, including: BRCA1 (3.4% vs 0.6%), TP53 (28.5% vs 21.1%), IGF1R (5.3% vs 1.5%), MYC (3.6% vs 1.3%), PPM1D (3.8% vs 1.4%), and GATA3 (19.5% vs 12.2%) (P&lt;0.01 for all comparisons). Conversely, alterations in the following genes were significantly higher in postM compared to preM HR+/HER2- BC samples: alterations in PIK3CA that serve as an FDA-approved companion diagnostic biomarker (CDx; 45.0% vs 35.5%) and PIK3CA non-CDx alterations (7.3% vs 4.5%) as well as ESR1 (8.8%% vs 5.1%), MAP3K1 (11.4% vs 7.4%), and CDH1 (18.5% vs 11.3%) alterations (P&lt;0.05 for all comparisons). In HER2+ BC, ESR1 alterations (5.1% vs 0.7%) were more frequent in postM compared to preM BC, while ERBB2 alterations were more frequent in preM compared to postM BC (79.9% vs 69.8%) (P&lt;0.05 for both comparisons). In TNBC, BRCA1 (18.8% vs 3.6%) and KIT (3.9% vs. 0.0%) alterations were significantly higher in preM compared to postM samples (P&lt;0.01 for both comparisons). BRCA1, IGF1R, and PPM1D alterations predominantly occurred in metastatic preM BC samples (P&lt;0.01 for all comparisons). Also, PIK3CA alterations predominantly occurred in primary postM BC, including both CDx (32.0%) and non-CDx (5.5%) alterations. ESR1 alterations, including mutations, fusions, and amplifications, were present in 21.8% of metastatic postM BC tumors, while ESR1 CDx mutations were found in 15.9% of these tumors. Conclusion: Our analysis uncovered therapeutically relevant differences in biomarker alterations between preM and postM BC. The higher frequency of ESR1 alterations in HR+/HER2- BC samples from postM women may indicate a resistance mechanism to AIs, as postM women with HR+ BC are commonly treated with this class of drugs. Additionally, the frequency of BRCA1 alterations was significantly higher in TNBC as well as HR+/HER2- preM BC. [CR1] [JH2]. I would eliminate this last sentence. This is intuitive and seems self-serving from a CGP-company. [CR1]agree -- at a minimum suggest replacing "increases" with "may have the potential to increase" Citation Format: Sameer Udhane, Pawan Noel, Fadel Alyaqoub, Ariane Kemkes, Cynthia Flannery, Nishitha Therala, Angela Deem, Jean-Paul De La O, Gargi Basu. Molecular landscape of breast cancer in pre- and postmenopausal women [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-03-30.

Abstract P2-05-18: Molecular effects of short pre-operative endocrine therapy in hormone receptor-positive and HER2-negative early breast cancer

2025-06-13

Raquel Gómez Bravo , Bárbara Adamo , Benjamín Walbaum +7 more | Clinical Cancer Research

Abstract Background: The identification of biomarkers for evaluating sensitivity to endocrine therapy in early breast cancer (EBC) is critical. Assessing the dynamic biological changes in the tumor caused by brief … Abstract Background: The identification of biomarkers for evaluating sensitivity to endocrine therapy in early breast cancer (EBC) is critical. Assessing the dynamic biological changes in the tumor caused by brief pre-operative endocrine therapy (POET) can guide decisions on reducing or intensifying treatment. In this study, we examined the molecular changes induced by short-term POET and their correlation with the treatment's effectiveness. Methods:This is a retrospective study of paired samples from patients (pts) with hormone receptor-positive and HER2-negative (HR+/HER2-) EBC treated at Hospital Clinic of Barcelona between 2014 and 2023 and from the letrozole arm of SOLTI-1501 VENTANA trial (Adamo et al. BCR 2019; NCT02802748). All pts received POET for 2 to 12 weeks prior to surgery, with tamoxifen or aromatase inhibitors (AI), administered according to menopausal status. RNA expression was assessed in baseline and surgery samples, including PAM50 and HER2DX signatures. Treatment response was defined as a value of Ki67≤10% at surgery. Logistic regression models explored the association between baseline gene expression and response. Gene expression changes were analyzed using paired SAM analysis and t-tests. Results: A total 111 pts with both baseline and surgery samples available were included. Median age was 63 years-old (61.8-66.4) and most of the tumors were cT1 (68.5%) and cN0 (97.3%) at diagnosis. 19 pts (17.1%) were premenopausal and 92 (82.9%) postmenopausal. The median baseline Ki67 was 18% (14-25%). After POET, the median Ki67 value was 4% (1-10). 81 pts (73%) reached Ki67≤10% at surgery and 41 (37%) Ki67≤ 2.7% (complete cell cycle arrest). At baseline, PAM50 molecular subtype distribution was: 79 pts (71.2%) Luminal A, 23 (20.7%) Luminal B, 4 (3.6%) HER2-enriched, 3 (2.7%) Normal-like, 2 (1.8%) Basal-like. At surgery, there were 82 (73.9%) Luminal A, 23 (20.7%) Normal-like, and 6 (5.4%) Basal-like tumors. In the univariate analysis, baseline clinicopathological variables associated with response were age (odds ratio [OR]=1.04, p=0.028), percentage of estrogen receptor (OR=1.03, p=0.025), Ki67 value (OR=0.95, p=0.003) and type of endocrine therapy (tamoxifen vs AI, OR=0.17, p&lt;0.001). In terms of baseline gene expression, high Luminal A signature (OR=7.72, p&lt;0.001) and luminal-related genes (e.g.: FOXA1 [OR=1.46, p=0.021] or ESR1 [OR=1.38, p=0.001]) were associated with response, while high Basal-like (OR=0.19, p=0.009), PAM50 proliferation (OR=0.30, p=0.005) and HER2DX proliferation (OR=0.24, p=0.037) signatures and proliferation-related genes (e.g.: MYBL2 [OR=0.58, p&lt;0.003] or MKI67 [OR=0.71, p=0.004]) were associated with no response. After POET, all genes and signatures were up- or downregulated significantly. In particular, we observed a significant decrease of the PAM50 Luminal and proliferation signatures, as well as the HER2DX proliferation and luminal signatures, with an increase of the HER2DX immune (IGG) and HER2 amplicon signatures, both in responders and non-responders (FDR&lt;5%). Conclusion: POET is a simple and secure treatment that can be administrated before surgery in HR+/HER2- EBC. The molecular profiling and dynamic evaluation of biological changes induced by POET could offer opportunities for a better understanding of the tumor´s sensitivity to endocrine therapy and could help guide and optimize treatment strategies in HR+/HER2- EBC. Citation Format: Raquel Gómez-Bravo, Barbara Adamo, Benjamin Walbaum, Esther Sanfeliu, Blanca González-Farré, Francesco Schettini, Olga Martínez-Sáez, Elia Seguí, Isabel García-Fructuoso, Paula Blasco, Oleguer Castillo, Ángela Aguirre, Valeria Sirenko, Pol Giménez, María Rey, Jordi Canes, Patricia Galván, Tomás Pascual, Maria Vidal, Adela Rodriguez Hernandez, Eva Ciruelos, Meritxell Bellet, Aleix Prat, Montserrat Muñoz, Fara Brasó-Maristany. Molecular effects of short pre-operative endocrine therapy in hormone receptor-positive and HER2-negative early breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-05-18.

Abstract P3-06-02: Prenatal diethylstilbestrol (DES) exposure and risk of benign breast disease

2025-06-13

Paloma R. Mitra , Kimberly A. Bertrand , Ruth M. Pfeiffer +7 more | Clinical Cancer Research

Abstract Introduction/Background: Diethylstilbestrol (DES), a synthetic estrogen and potent endocrine disruptor, was prescribed between the 1940s and 1970s to reduce risk of pregnancy complications and loss. DES was later found … Abstract Introduction/Background: Diethylstilbestrol (DES), a synthetic estrogen and potent endocrine disruptor, was prescribed between the 1940s and 1970s to reduce risk of pregnancy complications and loss. DES was later found to be associated with increased risk of vaginal and other cancers among those who were prenatally exposed and is thus no longer prescribed during pregnancy. Whether in utero DES exposure is also associated with subsequent risk of developing benign breast disease (BBD), a risk factor for breast cancer, is unknown, and evaluating the impact of DES may serve as a model of potential intergenerational chemical toxicity. We assessed the risk of developing BBD, overall and by histologic BBD subtype, associated with prenatal DES exposure. Methods: From the National Cancer Institute Combined DES Cohorts Follow-Up Study, we examined associations of prenatal DES exposure with BBD risk among 4208 DES-exposed and 1830 unexposed women born between 1933 and 1976. Prenatal DES exposure status was abstracted from medical records or physician notes, and cumulative high or low DES dose was assigned in cohorts with recorded regional prescribing patterns. BBD diagnoses were self-reported on questionnaires from 1990 to 2017. Pathology-confirmation of BBD was available for 600 out of 1086 self-reported BBD cases. Cox proportional hazards models with age as the time scale were used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for the association of DES exposure (DES unexposed, exposed) with BBD risk. Follow-up started at birth and ended at the earliest of a diagnosis of BBD or breast cancer, death, or loss to follow up; the baseline hazard was stratified by year of birth (1933-1951, 1952-1953, 1954-1957, 1958-1976) and cohort, and further adjusted for baseline questionnaire year (1994, 1997 or 2001) and number of questionnaires a woman had answered in a time-varying fashion. We estimated cumulative incidence of BBD by DES exposure status. In additional analyses, we censored women with a BBD diagnosis only obtained by self-report at the age of BBD, and considered risk by histologic BBD subtype (nonproliferative, proliferative without atypia, proliferative with atypia) separately. To test for heterogeneity of associations of DES exposure by histologic BBD subtype, we used case-only polytomous logistic regression models adjusted for follow-up time and year of reported BBD. Results: 6038 women contributed a total of 333,455 person-years with a median follow-up of 43.0 (range: 13.8-74.0) years for cases (n=1086) and 59.9 (range: 19.7-80.3) years for non-cases (n=4952). BBD diagnoses were confirmed by pathology among 225/350 (64%) unexposed women and 375/736 (51%) DES-exposed women. For the 600 BBD cases with pathologic confirmation, histology did not vary meaningfully by DES exposure: 54.7% nonproliferative, 32.1% proliferative without atypia, and 9.5% proliferative with atypia. Comparing women who were prenatally exposed to DES to unexposed women, we found no evidence of an association between DES exposure and risk of BBD (aHR: 0.98; 95%CI: 0.85, 1.12). There was no evidence of a dose-response relationship or difference in cumulative incidence by exposure status. The aHRs for nonproliferative BBD, proliferative BBD without atypia, and proliferative BBD with atypia were 0.83 (95%CI: 0.64, 1.07), 0.94 (95%CI: 0.67, 1.32), and 0.60 (95%CI: 0.33, 1.09), respectively, with no evidence of statistical heterogeneity by BBD subtype (p-heterogeneity: 0.86). Conclusions: The risk of BBD was not elevated among women who were exposed to DES in utero, suggesting that previously observed increases in breast cancer risk associated with DES are not likely meditated through this pathological mechanism. Citation Format: Paloma R. Mitra, Kimberly A. Bertrand, Ruth M. Pfeiffer, Julie R. Palmer, Soumya Ramireddy, Marianne Hyer, William C. Strohsnitter, Kjersti Aagaard, Dezheng Huo, Elizabeth E. Hatch, Linda Titus, Rebecca Troisi, Gretchen L. Gierach. Prenatal diethylstilbestrol (DES) exposure and risk of benign breast disease [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-06-02.

Abstract P3-05-23: Single nucleus chromatin accessibility and transcriptome analyses reveal aberrant inter-cellular communication in inflammatory breast cancer

2025-06-13

Harikrishna Nakshatri , Poornima Bhat‐Nakshatri , Cihat Erdoğan +2 more | Clinical Cancer Research

Abstract International efforts focused on discovery of biological targets in inflammatory breast cancer (IBC) have suggested that aberrant inter-cellular relationship instead of genomic aberrations is the key driver of IBC. … Abstract International efforts focused on discovery of biological targets in inflammatory breast cancer (IBC) have suggested that aberrant inter-cellular relationship instead of genomic aberrations is the key driver of IBC. To identify such IBC-specific aberrations, we generated single nucleus chromatin accessibility and transcriptome atlas of IBCs (9,628 nuclei from three donors) and compared IBC atlas with a similar atlas of the healthy breast (81,735 nuclei from 92 donors). We recently reported single nucleus atlas of breast tissues of healthy women of diverse genetic ancestry (Nature Medicine in press). In that report, we described markers that identify three major epithelial cell subtypes [Basal-myoepithelial (BM), luminal adaptive secretory precursor (LASP), luminal hormone sensing (LHS)], two endothelial cell subtypes, two adipocyte subtypes, fibroblasts, macrophages, and T cells of the healthy breast. We also showed that LHS cells are the likely cells-of-origin of Luminal A, Luminal B and HER2+ breast cancers. Unlike these breast cancer subtypes, IBC does not appear to have a cell-of-origin, as epithelial cells in IBCs shared gene expression pattern across BM, LASP and LHS cells. Similar results were obtained when comparison was restricted to ancestry-specific healthy breast atlas. However, individual gene level expression differences affecting specific signaling pathways were observed in epithelial cells of IBCs. LASP, and LHS cells of IBCs overexpressed GPR137C, a positive regulator of mTORC1 signaling, and HS6ST3, an enzyme required for heparan sulfate synthesis. LASP and LHS cells of IBCs displayed activation of mitotic and matrix metalloproteinase signaling, respectively. Endothelial cells of IBCs, which showed significant gene expression differences compared to endothelial cells of the healthy breast, displayed enhanced integrin cell surface interaction but loss of cell junction organization. Most critically, BM, LASP, LHS, and endothelial cells of IBCs compared to their counterparts in the healthy breast showed downregulation of TEX14, an inter-cellular bridge forming factor in germ cells and a regulator of mitosis. Downregulation of TEX14 expression in these cells was accompanied with changes in the chromatin accessibility patterns of this gene. These results reinforce the notion that defective inter-cellular communication is a hallmark of IBC and TEX14 expression levels may serve as a biomarker of this defect. We suggest that greater attention to vascular biology and vascular-epithelial cell communication has to be given for better understanding of IBC biology and therapeutic targeting. Citation Format: Harikrishna Nakshatri, Poornima Bhat-Nakshatri, Cihat Erdogan, Hongyu Gao, Yunlong Liu. Single nucleus chromatin accessibility and transcriptome analyses reveal aberrant inter-cellular communication in inflammatory breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-05-23.

Abstract PS16-05: Primary breast cancer prevention using oral endoxifen

2025-06-13

Per Hall , Stephen Nash , L. Magnus Bäcklund +5 more | Clinical Cancer Research

Abstract Estrogens play a crucial role in regulating the growth and differentiation of glandular cells in the breast. Tamoxifen blocks the effect of estrogens through binding to the estrogen receptor … Abstract Estrogens play a crucial role in regulating the growth and differentiation of glandular cells in the breast. Tamoxifen blocks the effect of estrogens through binding to the estrogen receptor thereby altering downstream signaling. Tamoxifen was approved by the U.S. Food and Drug Administration (FDA) in 1977 for the treatment of breast cancer. In 1997 the FDA accepted tamoxifen for prevention of breast cancer. Theapproval for prevention was based on results from several large randomized controlled trials targeting women aged 35 years or older with a 5-year breast cancer risk of 1.67% or higher. Despite tamoxifen’s success in reducing the recurrence risk of breast cancer, its systemic side effects have led to generally low acceptance. Also, the effect is heterogeneous because tamoxifen acts as a pro-drug that needs to be metabolization in the liver, primarily via the CYP2D6 enzyme. The most potent metabolite is endoxifen. Recent studies have shown that breast cancer patients who are poor or ultrarapid metabolizers have a worse outcome than intermediate and normal metabolizers. Poor metabolizers have too low endoxifen levels, while ultrarapid metabolizers often discontinue therapy due to unacceptable side effects. Additionally, common medications, such as selective serotonin reuptake inhibitors, influence CYP2D6 activity, altogether leading to a heterogeneity in tamoxifen efficacy. Endoxifen has been proposed as an alternative, not needing activation and not influenced by drug interactions. It has been shown that tamoxifen-induced mammographic density decrease is strongly associated with tamoxifen therapy response. Thus, a change in mammographic density could be used for evaluating the effect of endoxifen and / or tamoxifen. A density decrease could also theoretically be used to increase the sensitivity of a mammogram since density influences the ability to identify breast cancer on a mammogram. The ATOS-016R trial is a phase 2, randomized, double-blinded, placebo-controlled, study of oral (Z)-endoxifen (2 mg, 1 mg, and placebo; 80 women in each arm) in premenopausal women with measurable breast density. The trial invited women aged 40-55 years from three hospitals in Stockholm, Sweden. The primary objective is to determine if six months of daily (Z)-endoxifen can lead to a relative reduction in mammographic breast density area (cm2). The secondary objective is to assess the safety and tolerability of daily oral (Z)-endoxifen. The exploratory objectives are to: i) determine if daily oral (Z)-endoxifen for a maximum of six months results in at least a one-category reduction in the BI-RADS scale, ii) study the durability of (Z)-endoxifen effect on breast density response at 24 months post-standard of care screening mammogram, and iii) evaluate the levels of endoxifen over time and correlate endoxifen values to density change. Standard of care mammograms was used for the screening mammogram. Two study mammograms (each equivalent to the radiation dose of half a normal mammogram) was performed at 3 and 6 months. Clinical labs, vital signs, adverse events, and responses to questionnaires was used to assess safety and tolerability. The study was launched in December 2021, and the end of follow-up for the last of the 240 women is scheduled for June 14, 2024. Early results are expected in the fall of 2024. The ATOS-016R trial is a follow-up study to the KARISMA Low Dose Tamoxifen trial presented at SABCS in December 2023. In that trial, we showed that substantially lower doses of tamoxifen (2.5 mg) reduced mammographic density to the same extent as the established 20 mg dose. Severe side effects were reduced but reports of menopausal-like side effects associated with tamoxifen exposure were still substantial. Citation Format: Per Hall, Stephen Nash, Magnus Bäcklund, Jenny Bergqvist, Mattias Hammarström, Mikael Eriksson, Steven Quay, Kamila Czene. Primary breast cancer prevention using oral endoxifen [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS16-05.

Abstract P4-05-17: PER2 Expression as an Independent Predictor of Shorter Disease-Free Survival in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy

2025-06-13

Gabriela Bezerra Nobrega , Bruna Salani Mota , Rodrigo Gonçalves +7 more | Clinical Cancer Research

Abstract Background: The PERIOD2 (PER2) gene is a core component of the circadian clock and is crucial for maintaining daily rhythms. PER2, regulated by melatonin, is often linked to tumor … Abstract Background: The PERIOD2 (PER2) gene is a core component of the circadian clock and is crucial for maintaining daily rhythms. PER2, regulated by melatonin, is often linked to tumor development. Studies have shown that PER2 expression is downregulated in various tumors, and in vitro studies indicate that PER2 overexpression in tumor cells, including breast cancer cells, promotes apoptosis and reduces proliferation. Since melatonin interacts with estrogen receptors, hormone receptor status may influence PER2 expression. This study aimed to evaluate PER2 expression in different breast cancer (BC) molecular subtypes using immunohistochemistry (IHC) and to examine its association with disease-free survival (DFS) and overall survival (OS). Materials and Methods: A retrospective cohort study was conducted at the Instituto do Câncer do Estado de São Paulo from January 2012 to September 2023. The study included women with stages II-III BC, who completed neoadjuvant chemotherapy (NAC) followed by surgery. Following histological and immunohistochemical analysis, samples from 100 patients were classified into the following molecular subtypes: Triple-negative, Luminal A, Luminal B, HER2 enriched, and Luminal B – HER2+. IHC reactions using the primary antibody for PER2 (C6 -sc-377290 Santa Cruz Biotechnology, Inc.) were performed and qualitatively classified as follows: absence of expression, weak/moderate expression, and strong/intense expression of PER2. Two independent researchers analyzed the IHC results. Clinical, demographical and outcome data were extracted from electronic medical records. Associations between categorical variables were evaluated using the Chi-square test. OS and DFS were assessed using the Kaplan-Meier method and the Log-Rank test. Statistical significance was defined as p-values less than 0.05. Results: One hundred patients equally divided among Luminal A, Luminal B, HER2 enriched, Triple-negative and Luminal B – HER2+ molecular subtypes were selected. Five patients were excluded because of inadequate PER2 IHC staining. A total of 95 women were included, with a mean age of 54.4 years (range: 29-84) and a median BMI of 30.1 kg/m2. Additionally, 14.9% were nulliparous and 54.7% were post-menopausal. Before NAC, 28.4% of patients presented with stage II BC and 71.6% presented with stage III BC. 4.2% of the patients had absence of expression of PER2, 44.2% presented weak/moderate expression and 51.6% presented strong expression. There was no difference in PER2 expression according to molecular subtype (p=0.769). After NAC,18.1% of the patients achieved pathological complete response (pCR), with a statistically significant association between pCR and molecular subtype (p=0.001). At a median follow-up time of 90.2 months (IQR 62.6-123.9) there were 31 recurrence events (32.6%) and 29 overall deaths (30.5%). There was a statistically significant association between DFS and PER2 expression (log-rank p= 0.0288). Median DFS was 56.1 months (95%CI 28.3 – NR) for patients with no expression of PER2, 48.5 months (95%CI 24.6-81.8) for patients with moderate expression and 25 months (95%CI 15.7-37.7) for patients with strong expression of PER2. In a Cox multivariate analysis, adjusting for molecular subtype, PER2 expression remained associated with DFS with an HR of 3.02 (95% CI 0.52-17.481, p=0.22) for moderate expression and an HR of 13.13 (95% CI 1.89-91.15, p=0.009) for strong expression when compared to absence of expression. There was no statistically significant OS difference according to PER2 expression in our cohort (p=0.92). Conclusion: Our findings suggest that strong PER2 expression is an independent predictor of shorter DFS in breast cancer patients treated with NAC, highlighting its potential role as a prognostic biomarker. Further research is warranted to understand the underlying mechanisms and to explore potential therapeutic interventions targeting PER2 pathways. Citation Format: Gabriela Bezerra Nobrega, Bruna Salani Mota, Rodrigo Goncalves, Gabriela Boufelli de Freitas, Ricardo Hsieh, Silvia Vanessa Lourenço, Isaque da Silva Ferreira, Isabel Cristina Espósito Sorpreso, Bruna Karla Krislane Alves Costa Monteiro, José Cipolla-Neto, José Roberto Filassi, Edmund Chada Baracat, José Maria Soares Júnior. PER2 Expression as an Independent Predictor of Shorter Disease-Free Survival in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-05-17.

Abstract P2-03-17: Targeting NR2F2 overcomes multiple forms of endocrine resistance

2025-06-13

Yanyan Cai , Peihua Zhao , Fan Wu +7 more | Clinical Cancer Research

Abstract Endocrine resistance is frequently encountered in the clinic through a variety of mechanisms such as NF1 loss that induce alternative survival pathways and suppress estrogen responsiveness. While targeting the … Abstract Endocrine resistance is frequently encountered in the clinic through a variety of mechanisms such as NF1 loss that induce alternative survival pathways and suppress estrogen responsiveness. While targeting the induced pathways such as the RAS-MAPK pathway can have antitumor effects, it can also incur toxicities. To identify novel and potentially more specific therapeutic vulnerabilities in this context, we performed CRISPR/Cas9 screens in wildtype and NF1 knockout isogenic ER+ models and identified NR2F2, an orphan nuclear receptor, to be essential specifically in NF1 loss cells. Our in vitro and in vivo results revealed that NR2F2 is a critical regulator of the estrogen signaling pathway, largely playing a repressive role. We found that NF1 loss could upregulate NR2F2 expression level in ER+ breast cancer cells through the activation of the MAPK pathway. NR2F2 overexpression by itself conferred endocrine resistance, while genetic knockout and pharmacologic inhibition of NR2F2 sensitized ER+ breast cancer cells to endocrine therapies and attenuated resistance across multiple endocrine refractory tumor models including those driven by NF1 loss, ARID1A loss, and PTEN loss. These results reveal upregulation of NR2F2 to be a recurrent mechanism whereby hormone responsiveness is suppressed. At a mechanistic level, investigation into chromatin accessibility and transcription revealed that altered NR2F2 expression modulates genome-wide chromatin accessibility including ER-regulated loci and modulates ER transcriptional activity through its direct interactions with ER and its transcriptional coregulators. Collectively, our data unveil a critical mechanism whereby endocrine resistance occurs through the repression of estrogen responsiveness and highlight a new therapeutic approach to restore endocrine response through pharmacologic inhibition of NR2F2. Citation Format: Yanyan Cai, Peihua Zhao, Fan Wu, Huiyong Zhao, Hong Shao, Antonio Marra, Payal Patel, Elizabeth O’Connell, Emma Fink, Matthew M Miele, Zhuoning Li, Elisa De Stanchina, Emiliano Cocco, Pedram Razavi, Eneda Toska, Sean W Fanning, Guotai Xu, Anna A Sablina, Sarat Chandarlapaty. Targeting NR2F2 overcomes multiple forms of endocrine resistance [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-03-17.

Abstract P4-03-20: Molecular characterization of estrogen receptor (ER)+/HER2- breast cancer unveils a biologically and clinically distinct entity with ERBB2 hemizygous deletion (ERBB2del)

2025-06-13

Paolo Tarantino , Xintao Qiu , Rong Li +7 more | Clinical Cancer Research

Abstract Background: Among patients with ER+/HER2- breast cancer (BC), IHC-defined HER2-low and HER2-0 tumors do not appear to significantly differ molecularly (Tarantino P. et al. Nat Comm 2023). However, this … Abstract Background: Among patients with ER+/HER2- breast cancer (BC), IHC-defined HER2-low and HER2-0 tumors do not appear to significantly differ molecularly (Tarantino P. et al. Nat Comm 2023). However, this may be due to lack of sensitivity of IHC, which is currently used to select patients for T-DXd treatment, despite major diagnostic challenges. To better characterize the biologic correlates of HER2-low expression, we analyzed molecular profiles by quantitative ERBB2 mRNA expression and characterized the features of tumors harboring ERBB2del, for which resistance to T-DXd has been suggested. Methods: Genomic, transcriptomic and proteomic data from ER+/HER2- BCs were analyzed from the METABRIC, TCGA (early BC) and MSK MetTrospism (metastatic BC, MBC) databases. Genomic landscapes, gene expression and HER2 protein expression were compared between subgroups based on HER2 mRNA tertiles (ERBB2-low, -intermediate, -high), by HER2 IHC score (IHC 0, 1+, 2+/not amplified) and by ERBB2del. Further validation was conducted in two DFCI cohorts, including patients with HER2- early BC with tumors tested for OncotypeDX between 1/2018 - 12/2022 and patients with MBC with tumors that had undergone next-generation sequencing (NGS) between 7/2013 - 12/2020. Results: All ER+/HER2- BCs from the METABRIC (n=1298), TCGA (n=524) and early DFCI (n=971) cohorts exhibited some degree of ERBB2 mRNA expression. In both METABRIC and TCGA, the ERBB2 mRNA high group was enriched in pathways related to ER signaling (Hallmark estrogen response early), while the ERBB2 mRNA low group was enriched in genes involved in cell proliferation (Hallmark E2F targets, MYC targets) and immune response (Hallmark allograft rejection, TNF signaling via NF-kB, IFN-α response, IFN-γ response). At the genomic level, PIK3CA mutations were enriched in the ERBB2 mRNA-intermediate and -high groups (both p&lt;0.01), whereas TP53 mutations were enriched in the ERBB2 mRNA-low subgroup (p&lt;0.001). Notably, ERBB2del were common in the ERBB2 mRNA-low group of both METABRIC and TCGA (35% and 54%), but less frequent in the ERBB2 mRNA-intermediate and -high cohorts (METABRIC: 9% and 4%; TCGA: 14% and 5%). No significant difference in the distribution of PIK3CA, TP53 and ERBB2del was noted between HER2 IHC subgroups. Among tumors with ERBB2-low mRNA, &gt;90% of ERBB2del tumors had a concurrent TP53 heterozygous deletion (TP53del), compared with only 25-36% of non-ERBB2del tumors (both on chromosome 17). ERBB2del tumors were found enriched in the expression of genes related to cell proliferation and immune response, while non-ERBB2del BCs were enriched in genes related to ER signaling. ERBB2del tumors were found scattered across HER2 IHC subgroups (30.7% of IHC 0, 23.9% of IHC 1+, 15.8% of IHC 2+), had lower ERBB2 mRNA and HER2 protein levels, lower ER signaling and higher expression of proliferation genes within each HER2 IHC category. In the DFCI cohort of ER+/HER2- MBC with clinical NGS (n=749), the prevalence of ERBB2del was 14.3%, with 87.9% of ERBB2del tumors having concurrent TP53del. A significant difference in overall survival (OS) was observed between ERBB2del vs. non-ERBB2del tumors (33.8 vs 47.8 months, p=0.037), irrespective of the presence of TP53del, whereas no difference in OS was observed by HER2 IHC score (p=0.26). Similarly, in the MSK MetTrospism cohort (n=883), patients with ER+/HER2- MBC and an ERBB2del had worse OS (16.4 vs 30.8 months, p&lt;0.0001), while the presence of TP53del was not associated with OS (32.1 vs 34.2 months; p=0.62). Conclusions: ERBB2del are frequent events in ER+/HER2- BC that are characterized by low ERBB2 mRNA levels, and are associated with TP53del, higher proliferation and immunogenicity, lower ER signaling and HER2 protein expression, and decreased OS in the metastatic setting. Citation Format: Paolo Tarantino, Xintao Qiu, Rong Li, Albert Grinshpun, Hersh Gupta, Melissa E. Hughes, Gregory Kirkner, Lynette Sholl, Bruce E. Johnson, Matthew L. Meyerson, Andrew D. Cherniack, Yijia Jiang, Ningxuan Zhou, Nancy U. Lin, Henry W. Long, Sara M. Tolaney, Rinath M. Jeselsohn. Molecular characterization of estrogen receptor (ER)+/HER2- breast cancer unveils a biologically and clinically distinct entity with ERBB2 hemizygous deletion (ERBB2del) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-03-20.

Abstract P4-05-25: Impact of Estrogen Receptor Targeting Drugs on a Novel Epithelial-Mesenchymal Transition Pathway in Endocrine Resistant Breast Cancer: Implications for Metastasis

2025-06-13

Nivida Shete , Debra A. Tonetti | Clinical Cancer Research

Abstract Background: Approximately 10% of breast cancer patients are metastatic at the time of diagnosis with a 27% survival rate. Currently, endocrine therapy, including tamoxifen, aromatase inhibitors (letrozole, anastrozole, and … Abstract Background: Approximately 10% of breast cancer patients are metastatic at the time of diagnosis with a 27% survival rate. Currently, endocrine therapy, including tamoxifen, aromatase inhibitors (letrozole, anastrozole, and exemestane), Selective Estrogen Receptor Degraders (fulvestrant and elacestrant), is the standard of care for patients with estrogen receptor-positive (ER+) breast cancer. The major treatment challenge is endocrine therapy resistance and metastasis. Epithelial Mesenchymal Transition (EMT) is the process in which cells lose epithelial properties and acquire motility and mesenchymal phenotype, which leads to migration and invasion. EMT is characterized by the destabilization of adherens junctions by loss of E-cadherin at the plasma membrane. We previously reported a novel signaling pathway that is present in tamoxifen-resistant (TR) breast cancer cells. This pathway involves transcriptional repression of p120catenin by upstream regulators PKCa and FOXC2, resulting in the loss of E-cadherin at the plasma membrane (Pham, 2017). EMT features were characterized by decreased expression of epithelial markers and increased migration and invasion. Initially, estrogen stimulates breast cancer growth but becomes inhibitory after long-term estrogen deprivation. A novel Selective Human Estrogen Receptor Partial Agonist (ShERPA) TTC-352 is an estrogen mimic that induces unfolded protein response and shrinks the TR tumors (Molloy, 2014; Abderrahman, 2021). In this study, we investigated the impact of various ER-targeting drugs including 17b-estradiol (E2), tamoxifen, fulvestrant, and TTC-352 on the novel PKCa-FOXC2-p120catenin signaling axis. We hypothesize that ER-targeting drugs modulate the novel EMT pathway in TR breast cancer cells. Materials and Methods: TR cell lines used in this study include PKCa overexpressing cells MCF-7/PKCa, and MCF-7:5C and represent migratory ER+ breast cancer. Migration assays were performed in response to ER ligands using Falcon Permeable inserts. Migrated cells in response to chemoattractant were stained and counted after 24 hours. Luciferase reporter assays were performed to evaluate the effect of ER ligands on p120catenin transcription. Cells were transiently co-transfected with a p120catenin promoter-reporter plasmid using renilla vector for normalization. The reporter system readout is based on FOXC2 binding to the p120catenin promoter resulting in repression of luciferase transcription. Luciferase luminescence was measured on a plate reader corresponding to p120catenin transcription. Chromatin immunoprecipitation was performed using a FOXC2 antibody (Abcam-308055) to assess FOXC2 binding to the p120catenin promoter after ER ligand treatment. Results: E2 and TTC-352 treatment lowered FOXC2 binding on the p120catenin promoter, increased its transcription, and decreased the migration of MCF-7/PKCa and MCF-7:5C breast cancer cells compared to vehicle. E2 and TTC-352 treatment does not activate the PKCa-FOXC2-p120catenin EMT signaling axis and reduces the migratory potential of TR cells. Conclusion and Discussion: Our findings suggest that patients with endocrine-resistant ER+ breast cancer may benefit from E2 and TTC-352 therapy by inhibiting the activation of the PKCa-FOXC2-p120catenin signaling and cell migration identified in TR cell lines. Results of the Phase I clinical trial of TTC-352 reveal a reduced side effects profile and improved progression-free survival (Dudek, 2020). Strategizing less toxic treatment options may potentially reduce metastasis and prolong patient survival with a better quality of life. Citation Format: Nivida Shete, Debra A. Tonetti. Impact of Estrogen Receptor Targeting Drugs on a Novel Epithelial-Mesenchymal Transition Pathway in Endocrine Resistant Breast Cancer: Implications for Metastasis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-05-25.

Abstract P5-06-03: Single-cell and spatial approach to study endocrine therapy sensitivity in breast cancer models with heterogeneous estrogen receptor expression

2025-06-13

Svetlana E. Semina , Rosemary J. Huggins , Huiping Zhao +4 more | Clinical Cancer Research

Abstract Although most women with estrogen receptor (ER) positive breast tumors benefit from endocrine therapy (ET), up to 40% of these patients will experience relapse. The percentage of tumor cells … Abstract Although most women with estrogen receptor (ER) positive breast tumors benefit from endocrine therapy (ET), up to 40% of these patients will experience relapse. The percentage of tumor cells expressing ER varies from 1 to 100%, and some studies suggest that higher expression of ER positively correlates with ET efficiency and a reduced rate of tumor relapse. Previously, we identified a cell population with active NFĸB and integrated stress response pathways that overcome selective pressure of ET and contribute to tumor relapse. However, we and others routinely use models that are enriched for ER-expressing cells to study the ET effect. Less is known about ET efficacy in breast cancers with low to moderate ER expression, which are considered to be more aggressive. In this study, we utilized patient-derived xenograft organoids (PDxOs) and single-cell RNA sequencing (scRNAseq) approach to examine how breast cancer models with low to moderate ER expression respond to ET. Alongside established PDxOs (HCI003 and HCI017), we developed two new models (UIC013 and UIC020), where 22%, 30%, 12%, and 7% of cells express ERα, respectively. Using scRNAseq and various bioinformatic tools, we found several cell populations that are common among all models, but vary in terms of prevalence, as well as some populations that were largely model-specific, indicating the models’ inter- and intra- tumors heterogeneity. To predict which cell populations are sensitive to ET and which may harbor aggressive features, we examined well-established gene signatures for ER activity, ET resistance, and metastatic relapse in each cell cluster using Functional Enrichment Analysis. However, the results were inconclusive because of inconsistency among gene signatures, suggesting that the variety of models, platforms, and experimental setups used to derive these gene signatures could account for such variability. Additionally, these gene signatures were generated from bulk-RNA-seq studies, which average the signals obtained from all cell populations within a tumor and may mask signals from smaller cell populations. To experimentally identify ET-sensitive and ET-resistant cell populations, we treated each PDxO with fulvestrant and 4-hydroxytamoxifen. scRNAseq revealed that some ER-active cells were lost following ET, indicating responsiveness, while others remained unchanged or were enriched, indicating resistance to ET. Moreover, comparative analysis of all ET-resistant cell populations among the models showed their high degree of heterogeneity, suggesting that each cell population might use different mechanisms to overcome the selective pressure of ET. To find alternative therapies for the ET-resistant cells, we performed DREEP analysis (DRug Estimation from single-cell Expression Profile), a tool predicting drug responses for 450 compounds using scRNAseq data. Multiple compounds were predicted to be effective in combination with ET, including vandetanib, a VEGFR2 inhibitor currently in clinical trials with fulvestrant for metastatic breast cancer. ET also altered ER-resistant cell transcriptomes, predicting sensitivity to several additional compounds. Overall, our findings suggest that stratifying breast cancer cell populations based on ET response, rather than ER expression or activity alone, can identify new cell populations and therapeutic strategies, thereby improving outcomes for women with breast tumors with heterogeneous ER expression. Citation Format: Svetlana Semina, Rosemary J. Huggins, Huiping Zhao, Debra Tonetti, Kent Hoskins, Geoffrey L. Greene, Jonna Frasor. Single-cell and spatial approach to study endocrine therapy sensitivity in breast cancer models with heterogeneous estrogen receptor expression [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-06-03.

Abstract P2-03-07: Neoadjuvant (Z)-endoxifen for Premenopausal Estrogen Receptor (ER)+, Human Epidermal Growth Factor Receptor 2 (HER2)- Breast Cancer (BC): Evaluation of Quality of Life (QOL) measures in the EVANGELINE Study

2025-06-13

Sarah Premji , Vera J. Suman , Lida A. Mina +7 more | Clinical Cancer Research

Abstract Background: Premenopausal women (PrW) with ER+, HER2- breast cancer (BC) are commonly treated with aromatase inhibitors (AI) with ovarian function suppression (OFS) or tamoxifen (tam) +/- OFS. Common adverse … Abstract Background: Premenopausal women (PrW) with ER+, HER2- breast cancer (BC) are commonly treated with aromatase inhibitors (AI) with ovarian function suppression (OFS) or tamoxifen (tam) +/- OFS. Common adverse effects (AE) include musculoskeletal symptoms, hot flashes, night sweats, mood changes, and sexual side effects that may seriously impact quality of life (QOL). In SOFT, compared to tam alone, pts treated with tam + OFS had more hot flashes, loss of sexual interest, sleep disturbances, and vaginal dryness. In the combined SOFT/TEXT analysis, pts receiving exemestane + OFS had greater bone/joint pain, vaginal dryness, and loss of sexual interest, whereas pts receiving tam + OFS had more hot flushes and sweats. In the premenopausal setting, E1/E2 levels differ based on type of endocrine therapy regimen, with menopausal E1/E2 levels following OFS, but increases with tam monotherapy. EVANGELINE (NCT05607004) is an ongoing phase 2 multicenter neoadjuvant study assessing (Z)-endoxifen (ENDX), a potent tam metabolite that dually targets ERα and PKCβ, in PrW with ER+/HER2- BC. Prior to the randomized phase II, a PK run-in was designed to identify a dose wherein 28-day ENDX Css &gt; 500 ng/ml in ≥ 5/6 pts and to assess antitumor activity and toxicity when ENDX is dosed at 40 mg/day (monotherapy) and 80 mg/day (+/- OFS). Pts with endocrine sensitive disease (ESD) defined as 4-week Ki67 ≤ 10% continue treatment (tx) for 24 weeks followed by surgery. Here, we report the menopausal symptoms for pts enrolled onto 40 mg/day cohort. Methods: All eligible pts who completed baseline and at least one tx questionnaire or toxicity evaluation are included. Data captured by the medical team using Common Terminology Criteria for Adverse Events (CTCAE) and self-reported symptoms are reported in pts menstrual diary or on the Menopause-Specific Quality of Life (MENQOL) questionnaire administered at baseline, end of week 4, 12, and 24. MENQOL bothersomeness level was categorized as mild (score 0-1), moderate (2-4), and high (5-6). Estradiol and estrone levels were assessed for the 40 mg/day dose at week 4 and 24. Results: For the 40 mg/day cohort, 7 PrW (6 White, 1 Asian) aged 28-51 (median 46) received ENDX. One pt discontinued due to week 4 Ki-67 &gt; 10%. The remaining 6 had ESD, and after 24 weeks underwent surgery. Over the course of tx, relevant AEs reported as possibly, probably or definitely attributed to ENDX included: amenorrhea (G2-n=5); dysmenorrhea (G2-n=1; G1-n=1), hot flashes (G2-n=1; G1-n=5), hyperhidrosis (G1-n=1), hypomenorrhea (G1-n=1), irregular menstruation (G1-n=2), and libido decrease (G2-n=1). Menses did not occur on tx for 4 pts. No dose reductions occurred. Among the remaining 3 pts, dysmenorrhea was described as mild/moderate. MENQOL after 4 wks of tx revealed that hot flashes developed in 4 pts (moderately bothersome -3 pts, not bothersome -1 pt). One pt began venlafaxine for hot flashes. Three pts reported ‘being impatient with others’ as moderately bothersome. The median (range) baseline estrone (n=5) was 54 pg/mL (19-114) with median (range) fold increase from baseline of 9.0 (1.3-23.2 pg/mL) at wk4 and 4.7 (0.4 - 25.9 pg/mL) at wk24. The median baseline estradiol level (n=5) was 29 pg/mL (19-209) with median fold increases from baseline of 17.9 (0.4-57.0 pg/mL) at wk4 and 8.1 (0.04 - 56.6 ng/mL) at wk24. Currently, 12 pts are enrolled to either 80 mg/day monotherapy or 80 mg/day + OFS. Conclusions: This is the first report of menopausal side effects in PrW women treated with ENDX 40 mg/day without OFS. Most side effects were low grade and amenorrhea was common. ENDX induced marked increases in E1/E2 levels that peaked at 4 weeks and then declined. MENQOL data from the 80 mg/day monotherapy and 80 mg/day + OFS cohort will be reported at the meeting. Citation Format: Sarah K. Premji, Vera J. Suman, Lida A. Mina, Pooja P. Advani, Arezoo Mirad, Roberto Leon-Ferre, Karthik V. Giridhar, Felipe Batalini, Swaathi Jayaraman, Patricia Cronin, Mara Piltin, Amy Degnim, James N. Ingle, Tufia C. Haddad, Amye J. Tevaarwerk, Jason M. Jones, Daniel Flora, Harjinder Singh, Nusayba A. Bagegni, Katie N. Hunt, Judy C. Boughey, Joel M. Reid, Matthew Schellenberg, John R. Hawse, Steven Carl Quay, Matthew P. Goetz. Neoadjuvant (Z)-endoxifen for Premenopausal Estrogen Receptor (ER)+, Human Epidermal Growth Factor Receptor 2 (HER2)- Breast Cancer (BC): Evaluation of Quality of Life (QOL) measures in the EVANGELINE Study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-03-07.

Estrogen receptor alpha dynamics and plasticity during endocrine resistance

2025-06-13

Aswathy Sivasailam , K. Santosh Kumar , Aparna Geetha Jayaprasad +7 more | Biology Direct

Abstract P2-08-15: From Clinical Trials to Real-World Practice: Treatment Regimens, Pathological Complete Response Rates, and the Addition of Platinum Salts in Patients with Triple- Negative Breast Cancer

2025-06-13

Maria Eleni Hatzipanagiotou , Verena Zeltner , Michael Gerken +6 more | Clinical Cancer Research

Abstract Purpose: Comprehensive real-world data on current treatment methods for early triple- negative breast cancer (TNBC) are limited. To validate optimal treatments demonstrated in randomized controlled trials analyses of data … Abstract Purpose: Comprehensive real-world data on current treatment methods for early triple- negative breast cancer (TNBC) are limited. To validate optimal treatments demonstrated in randomized controlled trials analyses of data obtained from routine clinical care are essential. This study aims to analyze the treatment outcomes of patients with early-stage TNBC using data from a large, population-based cancer registry. Methods: This retrospective, non-interventional, population-based singlemulti-center study utilized data from TNBC patients diagnosed between January 1, 2010, and December 31, 2018, at the cancer registry Tumor Centre Regensburg. The data included demographics, pathology, treatment, recurrence, and survival, with follow-up extending to December 2023. 319 patients with TNBC who received neoadjuvant chemotherapy were identified. The outcomes measured were pathologic complete response (pCR), overall survival (OS), and recurrence-free survival (RFS). Results: A total of 319 patients were included. Of these, 132 (41.4%) received neoadjuvant chemotherapy (NACT) with Epirubicin/Cyclophosphamide (EC) and Paclitaxel (EC-T), 74 (23.2%) received NACT with EC-T and Platinum (EC-P/T), and 22 (6.9%) received NACT with EC-P/nabPaclitaxel (EC-P/nabP). Other NACT protocols were administered to 91 (28.5%) patients. A pCR was achieved in 49.8% of NACT patients, with a rate of 37.1% in the subgroup without platinum. The addition of platinum significantly increased the pCR rate to 54.1% compared to EC-T (OR 3.476, 95% CI 1.655-7.300, p=0.001). EC-P/nabP led to a significant increase in the pCR rate to 77.3% (OR 8.767, 95% CI 2.421-31.744, p&lt;.001). Conclusion: This real-world evidence study demonstrates the increased use of platinum- based neoadjuvant therapies in alignment with current clinical guidelines, resulting in higher pCR rates. This trend is consistent with findings from randomized controlled trials. Platinum salts should be a standard of care in the chemotherapy regiments for patients with TNBC. Citation Format: Maria Eleni Hatzipanagiotou, Verena Zeltner, Michael Gerken, Miriam Pigerl, Sophie Räpple, Jonas Roth, Olaf Ortmann, Monika Klinkhammer-Schalke, Stephan Seitz. From Clinical Trials to Real-World Practice: Treatment Regimens, Pathological Complete Response Rates, and the Addition of Platinum Salts in Patients with Triple- Negative Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-08-15.

Interplay of Receptor Status, Age, and Stage in Breast Cancer: A Prospective Analysis

2025-06-13

Mariam Malik , Zeeshan Rashid Mirza , Rana Bilal Idrees +5 more | Cureus