scholarly journals Differential Genomic Interactions Drive Progesterone Receptor Isoform Specific Functions in Breast Cancer

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A821-A821
Author(s):  
Tram B Doan ◽  
J Dinny Graham ◽  
Mariah Tehan ◽  
Barbara J Guild ◽  
Christine L Clarke
Keyword(s):  
Breast Cancer ◽  
Progesterone Receptor ◽  
Hormone Replacement ◽  
Breast Cancer Incidence ◽  
Normal Breast ◽  
Breast Development ◽  
Integrated Analysis ◽  
Breast Cancers ◽  
Multiple Cancer ◽  
Breast Cancer Outcome

Abstract Progesterone is critical for normal breast development and function, and has been shown to stimulate proliferation of normal breast epithelial cells by increasing stem and progenitor cell numbers. Breast cancer incidence is increased in women exposed to progesterone analogues in combined estrogen plus progestin hormone replacement therapy, but not in women taking estrogen alone. Classical progesterone signaling is mediated through the nuclear progesterone receptor (PR), which occurs as two related but functionally different isoforms, PRA and PRB. PRA and PRB are co-expressed equally in normal breast tissue but become dysregulated in breast cancer where PRA often becomes predominant. PRA predominance in breast cancer is associated with poorer outcome and higher risk of distant metastasis in tamoxifen treated patients. We show using integrated analysis of ChIP-seq, ATAC-seq and transcriptomic profiling in a breast cancer cell line model of acquired PRA predominance that: 1) PRA and PRB have different requirements with regard to chromatin accessibility; 2) PRA predominance reshapes the PR cistrome and the associated transcriptome to affect genes not normally regulated by PR when PRA and PRB are equivalently expressed, possibly through assisted loading with multiple other transcription factors; 3) Genes regulated by PR only when PRA is predominant are associated with poorer breast cancer outcome and involved in multiple cancer-associated pathways including those that regulate cell proliferation and adhesion. Our data suggest a mechanism for the poorer disease outcome seen in breast cancers with a predominance of PRA.

scholarly journals Estrogen receptor subtypes dictate the proliferative nature of the mammary gland

2018 ◽  
Vol 237 (3) ◽  
pp. 323-336 ◽  
Author(s):  
Genevieve V Dall ◽  
Samuel Hawthorne ◽  
Yashar Seyed-Razavi ◽  
Jessica Vieusseux ◽  
Wanfu Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Breast Cancer Diagnosis ◽  
Normal Breast ◽  
Breast Development ◽  
Receptor Subtypes ◽  
Breast Cancers ◽  
Proliferative Effect

Estrogen induces proliferation of breast epithelial cells and is responsible for breast development at puberty. This tightly regulated control is lost in estrogen-receptor-positive (ER+) breast cancers, which comprise over 70% of all breast cancers. Currently, breast cancer diagnosis and treatment considers only the α isoform of ER; however, there is a second ER, ERβ. Whilst ERα mediates estrogen-driven proliferation of the normal breast in puberty and breast cancers, ERβ has been shown to exert an anti-proliferative effect on the normal breast. It is not known how the expression of each ER (alone or in combination) correlates with the ability of estrogen to induce proliferation in the breast. We assessed the levels of each ER in normal mouse mammary glands subdivided into proliferative and non-proliferative regions. ERα was most abundant in the proliferative regions of younger mice, with ERβ expressed most abundantly in old mice. We correlated this expression profile with function by showing that the ability of estrogen to induce proliferation was reduced in older mice. To show that the ER profile associated with breast cancer risk, we assessed ER expression in parous mice which are known to have a reduced risk of developing ERα breast cancer. ERα expression was significantly decreased yet co-localization analysis revealed ERβ expression increased with parity. Parous mice had less unopposed nuclear ERα expression and increased levels of ERβ. These changes suggest that the nuclear expression of ERs dictates the proliferative nature of the breast and may explain the decreased breast cancer risk with parity.

scholarly journals ER81 Expression in Breast Cancers and Hyperplasia

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
YuanYuan Wang ◽  
Li Wang ◽  
Yue Chen ◽  
Lin Li ◽  
XuanTao Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Stage ◽  
Statistical Significance ◽  
Normal Breast ◽  
Breast Development ◽  
Breast Cancers ◽  
Breast Carcinogenesis ◽  
Cancer Tissues ◽  
Breast Tissues

ER81 is a transcription factor that may contribute to breast cancer; however, little known about the role of ER81 in breast carcinogenesis. To investigate the role of ER81 in breast carcinogenesis, we examined ER81 expression in IDC, DCIS, ADH, HUT, and normal breast tissues by immunohistochemical staining. We found that ER81 overexpression was detected in 25.7% (9/35) of HUT, 41.2% (7/17) of ADH, 54.5% (12/22) of DCIS, and 63.0% (51/81) of IDC. In 20 of breast cancer tissues combined with DCIS, ADH, and HUT, ER81 expression was found in 14/20 (70%) IDC. In these 14 cases all cases were ER81 positive expression in DCIS, 13 of 14 cases were positively expressed of ER81 in ADH and 8 of 14 were positive for ER81 in HUT components. A statistical significance was found between NBT and HUT () and HUT and ADH (). Clinical-pathological features analysis of breast cancer revealed that ER81 expression was significantly associated with Her2 amplification and was negatively associated with ER and PR expression. Our results demonstrated that ER81 overexpression was present in the early stage of breast development that suggested that ER81 overexpression may play an important role in breast carcinogenesis.

A new genomic approach to describe the natural history of node negative breast cancer patients

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10058-10058
Author(s):  
M. Saghatchian ◽  
R. Lidereau ◽  
S. Delaloge ◽  
S. Koscielny ◽  
A. Kauffmann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prediction Accuracy ◽  
Complex Disease ◽  
Statistical Significance ◽  
Normal Breast ◽  
Benign Tumors ◽  
Consecutive Series ◽  
Breast Cancers ◽  
Node Negative ◽  
Breast Cancer Outcome

10058 Background: Breast cancer is a heterogeneous and complex disease beyond good/bad prognosis groups. Previous studies identified prognostic tools that are undergoing inter-group validation. Our present study aims at better defining pre-malignant vs. malignant lesions and tumors that will give local vs. distant metastases (DM) or early vs. late DM. Methods: We selected 3 groups of patients (pts) in a consecutive series of node-negative breast cancers with a very long follow-up (>10 years (y)) and available frozen tumor samples. Pts who did not receive any adjuvant treatment were selected: 60 with no relapse after 10 y, 29 with early DM before 5 y and 18 with late DM after 5y. Genomic profiling on 44K Agilent pangenomic arrays taking as reference non-relapsing pts (after 10y) or normal breast (Clonetech) allowed us to select specific genes related to DM occurrence or tumorigenesis. Random permutations were performed to assess the statistical significance of our prediction accuracy. Results: 1- we identified a 141 gene-profile and related genes distinguishing tumors with early DM from tumors with late DM (71% prediction accuracy). 2- Similarly, we identified a 285-gene signature for late DM vs. no relapse at 10 y (80% prediction accuracy). Genes were further classified according to family clusters allowing description of genes involved in DM occurrence. 3- a total of 435 genes were also significantly over-expressed in at least 90% of 148 tumours (compared to normal breast). Among those, a selection of the most significant genes were analysed for RT-PC expression throughout the various steps of tumour development (normal breast, benign tumors, in situ carcinomas, invasive carcinomas). Among the 15 most upregulated genes listed, 3 unknown genes appear, that are overexpressed in 98% of the tumors with an average fold change > 11 and are currently explored. Discussion: In this unique series of untreated node-negative breast cancers, identification of molecular profiles of early and late DM could be useful in better early prediction of breast cancer outcome. Based on genomic analysis, a molecular gene based classification of progression from benign tissue to aggressive tumors allows to dissect pathways towards malignancy and to identify early diagnostic markers or targets for prevention. No significant financial relationships to disclose.

scholarly journals Progesterone and Breast Cancer

2008 ◽  
Vol 4 (2) ◽  
pp. 151-162 ◽  
Author(s):  
Carol A Lange ◽  
Douglas Yee
Keyword(s):  
Breast Cancer ◽  
Steroid Hormone ◽  
Hormone Replacement ◽  
Reproductive Organs ◽  
Normal Breast ◽  
Breast Development ◽  
Cancer Therapies ◽  
First Line ◽  
The Brain

Progesterone is an ovarian steroid hormone that is essential for normal breast development during puberty and in preparation for lactation and breastfeeding. The actions of progesterone are primarily mediated by its high-affinity receptors, which include the classical progesterone receptor (PR)-A and -B isoforms, located in diverse tissues, including the brain, where progesterone controls reproductive behavior, and the breast and reproductive organs. Progestins are frequently prescribed for contraception or during postmenopausal hormone replacement therapy, in which progestins are combined with estrogen as a means to block estrogen-induced endometrial growth. The role of estrogen as a potent breast mitogen is undisputed, and inhibitors of the estrogen receptor and estrogen-producing enzymes (aromatases) are effective first-line cancer therapies. However, PR action in breast cancer is grossly understudied and remains controversial. Herein, we review existing evidence and discuss the challenges to defining a role for progesterone in breast cancer.

scholarly journals Estrogens and Progestogens in Triple Negative Breast Cancer: Do They Harm?

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2506
Author(s):  
Mark van Barele ◽  
Bernadette A. M. Heemskerk-Gerritsen ◽  
Yvonne V. Louwers ◽  
Mijntje B. Vastbinder ◽  
John W. M. Martens ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Hormone Replacement ◽  
Breast Cancers ◽  
Younger Women ◽  
Alternative Pathways ◽  
Increased Risk ◽  
History Of ◽  
Hormone Sensitive

Triple-negative breast cancers (TNBC) occur more frequently in younger women and do not express estrogen receptor (ER) nor progesterone receptor (PR), and are therefore often considered hormone-insensitive. Treatment of premenopausal TNBC patients almost always includes chemotherapy, which may lead to premature ovarian insufficiency (POI) and can severely impact quality of life. Hormone replacement therapy (HRT) is contraindicated for patients with a history of hormone-sensitive breast cancer, but the data on safety for TNBC patients is inconclusive, with a few randomized trials showing increased risk-ratios with wide confidence intervals for recurrence after HRT. Here, we review the literature on alternative pathways from the classical ER/PR. We find that for both estrogens and progestogens, potential alternatives exist for exerting their effects on TNBC, ranging from receptor conversion, to alternative receptors capable of binding estrogens, as well as paracrine pathways, such as RANK/RANKL, which can cause progestogens to indirectly stimulate growth and metastasis of TNBC. Finally, HRT may also influence other hormones, such as androgens, and their effects on TNBCs expressing androgen receptors (AR). Concluding, the assumption that TNBC is completely hormone-insensitive is incorrect. However, the direction of the effects of the alternative pathways is not always clear, and will need to be investigated further.

ARE BREAST CANCERS IN PATIENTS ON HORMONE REPLACEMENT THERAPY DIFFERENT FROM THE CLASSICAL BREAST CANCER?

2003 ◽  
Vol 13 (Suppl 1) ◽  
pp. 30.1-30
Author(s):  
M. Aerts ◽  
P. Neven ◽  
R. Drijkoningen ◽  
L. Morales ◽  
R. Paridaens ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Replacement Therapy ◽  
Replacement Therapy ◽  
Hormone Replacement ◽  
Breast Cancers

Male Versus Female Breast Cancers

2003 ◽  
Vol 127 (1) ◽  
pp. 36-41 ◽  
Author(s):  
D. Muir ◽  
R. Kanthan ◽  
S. C. Kanthan
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Progesterone Receptor ◽  
Male Breast Cancer ◽  
Male Breast ◽  
High Grade ◽  
Breast Cancers ◽  
Receptor Status ◽  
Female Breast ◽  
Grade 3

Abstract Context.—The rate of male breast cancer is a small fraction of that observed in females, thus severely limiting our understanding of the pathogenesis of this condition. It remains unclear whether the biological behavior and tumor progression associated with male breast cancer parallel that of the female form. Objectives.—To evaluate the immunohistochemical profile of male breast carcinomas and to compare this profile with that of stage-matched female breast cancers. Design.—Seventy-five cases of primary male breast cancer were identified using the records of the Saskatchewan Cancer Foundation over a period of 26 years (1970–1996). Fifty-nine of these cases had formalin-fixed, paraffin-embedded tissue blocks available for the purposes of this study. All cases were reviewed and a standardized modified Bloom-Richardson grading criterion was applied. Estrogen receptor status, progesterone receptor status, c-Erb-B2 expression, p53 expression, and Bcl-2 expression were evaluated by immunohistochemistry. Results from 240 consecutive cases of stage-matched female breast cancers analyzed in the same laboratory were used as a standard set for comparison. Results.—Male breast cancers tended to be high grade (85% grade 3) in comparison with the female breast cancers (50% grade 3). In descriptive analysis across all stages of disease, male carcinomas were more frequently estrogen receptor positive (81% vs 69%) than their female counterparts. Despite their high grade, they were less likely to overexpress p53 (9% vs 28%) and Erb-B2 (5% vs 17%) than the female counterparts. There was no significant difference in either progesterone receptor (63% vs 56%) or Bcl-2 (79% vs 76%) overexpression. Stratified analysis by stage-matched controls showed no statistically significant differences among the men and women with stage I disease. However, in stage II–matched samples, statistically significant differences were observed between the 2 groups. The male cancers were more likely to overexpress estrogen receptor (81.6% vs 64.4%, P = .04), progesterone receptor (71.1% vs 47.5%, P = .01), and Bcl-2 (78.9% vs 69.4%, P = .20). They also showed statistically significant lower expression of p53 (7.9% vs 36.3%, P = .001) and Erb-B2 (5.3% vs 23.8% P = .01). Conclusion.—Male breast cancers display distinct immunophenotypic differences from those occurring in women, implying a different pathogenesis in the evolution and progression of this disease. Such differences may play key roles in therapeutic management, warranting different treatment strategies in comparison to female breast cancers.

Predominance of RAD21 and ERBB2 amplification and progesterone receptor positivity in tumors of the right breast support breast cancer lateralization.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e12557-e12557
Author(s):  
Zachary Spigelman ◽  
Jo-Ellen Murphy
Keyword(s):  
Breast Cancer ◽  
Progesterone Receptor ◽  
Cancer Patients ◽  
Breast Tumors ◽  
Left Breast ◽  
Breast Cancers ◽  
Her2 Expression ◽  
Breast Cancer Patients ◽  
The Right ◽  
Chi Square Analysis

e12557 Background: Biologic lateralization broadly impacts breast cancer. Malignancies originating in the left breast compared to the right breast tend to be more frequent, larger and of poorer prognosis. Left breast tumors respond differently to HER2-neu signaling and have lateralized Ki67 expression. In a prior study a right-left asymmetry in the neutrophil/lymphocyte ratio (NLR) of breast cancers was identified (ASCO 2018, e13094). As a follow-up, retrospective analysis of results from comprehensive genomic profiling (CGP) of right and left side breast cancer specimens was performed to determine a potential genomic etiology for the observed NLR lateralization. Methods: Tumors from 43 consecutive breast cancer patients underwent analysis for all classes of genomic alterations by hybrid capture-based CGP (Foundation Medicine). The CGP results from the 25 left- and 18 right-sided breast cancer samples were analyzed along with the histologic grade and status of estrogen receptor (ER), progesterone receptor (PR), and HER2 expression. Results: In this cohort of advanced breast cancer patients (stage 3-4), no statistically significant differences in lateralization were identified based on patient age, tumor stage, or frequency of ER or Her2 expression (Table). A predominance of PR positivity (p=0.14 chi square analysis) and amplifications in the ERBB2 (p=0.37) and RAD21 (p=0.08) genes were detected in right side tumors. Conclusions: Together with the prior study, trends in asymmetry based on genomic, pathologic, and immunohistologic differences have been detected in breast cancers, including an increased incidence of ERBB2 and RAD21 amplification in right-side breast tumors in this cohort. The predominance of lower PR positivity in the left breast tumors may be due to preferential hypermethylation, consistent with reports that it mediates biologic lateralization changes, downregulates PR expression, and alters amplification rates. Epigenetic methylation, may contribute to asymmetric breast cancer biology and have implications for therapeutic strategy. Further study is warranted.[Table: see text]

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