Progesterone Receptor Isoform Functions in Normal Breast Development and Breast Cancer

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.

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Bringing androgens up a NOTCH in breast cancer

Endocrine Related Cancer ◽

10.1530/erc-14-0248 ◽

2014 ◽

Vol 21 (4) ◽

pp. T183-T202 ◽

Cited By ~ 19

Author(s):

Gerard A Tarulli ◽

Lisa M Butler ◽

Wayne D Tilley ◽

Theresa E Hickey

Keyword(s):

Breast Cancer ◽

Epithelial Cells ◽

Normal Breast ◽

Notch Signalling ◽

Breast Development ◽

Breast Epithelium ◽

Breast Epithelial Cells ◽

Androgen Action ◽

Breast Epithelial

While it has been known for decades that androgen hormones influence normal breast development and breast carcinogenesis, the underlying mechanisms have only been recently elucidated. To date, most studies have focused on androgen action in breast cancer cell lines, yet these studies represent artificial systems that often do not faithfully replicate/recapitulate the cellular, molecular and hormonal environments of breast tumoursin vivo. It is critical to have a better understanding of how androgens act in the normal mammary gland as well as inin vivosystems that maintain a relevant tumour microenvironment to gain insights into the role of androgens in the modulation of breast cancer development. This in turn will facilitate application of androgen-modulation therapy in breast cancer. This is particularly relevant as current clinical trials focus on inhibiting androgen action as breast cancer therapy but, depending on the steroid receptor profile of the tumour, certain individuals may be better served by selectively stimulating androgen action. Androgen receptor (AR) protein is primarily expressed by the hormone-sensing compartment of normal breast epithelium, commonly referred to as oestrogen receptor alpha (ERa (ESR1))-positive breast epithelial cells, which also express progesterone receptors (PRs) and prolactin receptors and exert powerful developmental influences on adjacent breast epithelial cells. Recent lineage-tracing studies, particularly those focussed on NOTCH signalling, and genetic analysis of cancer risk in the normal breast highlight how signalling via the hormone-sensing compartment can influence normal breast development and breast cancer susceptibility. This provides an impetus to focus on the relationship between androgens, AR and NOTCH signalling and the crosstalk between ERa and PR signalling in the hormone-sensing component of breast epithelium in order to unravel the mechanisms behind the ability of androgens to modulate breast cancer initiation and growth.

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Methylation of progesterone receptor isoform A promoter in normal breast tissue: An epigenetic link between early age at menarche and risk of breast cancer?

Journal of Cellular Biochemistry ◽

10.1002/jcb.28505 ◽

2019 ◽

Vol 120 (8) ◽

pp. 12393-12401 ◽

Cited By ~ 2

Author(s):

Abdolreza Daraei ◽

Pantea Izadi ◽

Ghasemali Khorasani ◽

Nahid Nafissi ◽

Mohammad Mehdi Naghizadeh ◽

...

Keyword(s):

Breast Cancer ◽

Progesterone Receptor ◽

Breast Tissue ◽

Normal Breast Tissue ◽

Normal Breast ◽

Age At Menarche ◽

Early Age

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Estrogen receptor subtypes dictate the proliferative nature of the mammary gland

Journal of Endocrinology ◽

10.1530/joe-17-0582 ◽

2018 ◽

Vol 237 (3) ◽

pp. 323-336 ◽

Cited By ~ 15

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.

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Progesterone receptors in normal breast development and breast cancer

Essays in Biochemistry ◽

10.1042/ebc20200163 ◽

2021 ◽

Author(s):

Sebastian Giulianelli ◽

Caroline A. Lamb ◽

Claudia Lanari

Keyword(s):

Breast Cancer ◽

Clinical Trials ◽

Progesterone Receptors ◽

Hormone Treatment ◽

Normal Breast ◽

Cancer Prognosis ◽

Breast Development ◽

Cancer Growth ◽

Breast Cancer Growth

Abstract Progesterone receptors (PR) play a pivotal role in many female reproductive tissues such as the uterus, the ovary, and the mammary gland (MG). Moreover, PR play a key role in breast cancer growth and progression. This has led to the development and study of different progestins and antiprogestins, many of which are currently being tested in clinical trials for cancer treatment. Recent reviews have addressed the role of PR in MG development, carcinogenesis, and breast cancer growth. Thus, in this review, in addition to making an overview on PR action in normal and tumor breast, the focus has been put on highlighting the still unresolved topics on hormone treatment involving PR isoforms and breast cancer prognosis.

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Expression of estrogen receptor, progesterone receptor, and Ki67 in normal breast tissue in relation to subsequent risk of breast cancer

npj Breast Cancer ◽

10.1038/npjbcancer.2016.32 ◽

2016 ◽

Vol 2 (1) ◽

Cited By ~ 16

Author(s):

Hannah Oh ◽

A Heather Eliassen ◽

Molin Wang ◽

Stephanie A Smith-Warner ◽

Andrew H Beck ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Progesterone Receptor ◽

Breast Tissue ◽

Normal Breast Tissue ◽

Normal Breast ◽

Subsequent Risk

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ER81 Expression in Breast Cancers and Hyperplasia

Pathology Research International ◽

10.4061/2011/980513 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 10

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.

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Abstract LB-179: Expression of estrogen receptor, progesterone receptor, and ki67 in normal breast tissue and subsequent risk of breast cancer

10.1158/1538-7445.am2015-lb-179 ◽

2015 ◽

Author(s):

Hannah Oh ◽

A Heather Eliassen ◽

Molin Wang ◽

Stephanie A. Smith-Warner ◽

Andrew H. Beck ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Progesterone Receptor ◽

Breast Tissue ◽

Normal Breast Tissue ◽

Normal Breast ◽

Subsequent Risk

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Cyclin D1 Enhances the Response to Estrogen and Progesterone by Regulating Progesterone Receptor Expression

Molecular and Cellular Biology ◽

10.1128/mcb.01398-09 ◽

2010 ◽

Vol 30 (12) ◽

pp. 3111-3125 ◽

Cited By ~ 12

Author(s):

Chuanwei Yang ◽

Li Chen ◽

Cuiqi Li ◽

Mary C. Lynch ◽

Cathrin Brisken ◽

...

Keyword(s):

Breast Cancer ◽

Progesterone Receptor ◽

Cyclin D1 ◽

Receptor Gene ◽

Receptor Expression ◽

Breast Development ◽

Normal Female ◽

Progesterone Receptor Expression ◽

Breast Carcinogenesis ◽

Dna Encoding

ABSTRACT Estrogen and progesterone are the defining hormones of normal female development, and both play critical roles in breast carcinogenesis. Cyclin D1 is a breast cancer oncogene whose amplification is linked to poor prognosis in estrogen and progesterone receptor-positive breast cancers. Here we report that cyclin D1 regulates progesterone receptor expression, consequently enhancing responses to estrogen and progesterone. Estrogen treatment of cyclin D1 transgenic mice increased progesterone receptor expression and induced mammary hyperplasias that were stimulated by progesterone and blocked by a progesterone antagonist. Progesterone receptor levels decreased in cyclin D1 knockout mice. Cyclin D1 regulated progesterone receptor expression through a novel estrogen- and cyclin D1-responsive enhancer in DNA encoding part of the 3′ untranslated region of the progesterone receptor gene. Small inhibitory RNAs for cyclin D1 decreased progesterone receptor expression and estrogen receptor binding to the 3′ enhancer region in human breast cancer cells. Since estrogen and progesterone regulate cyclin D1, our results suggest that cyclin D1's participation in a feed-forward loop could contribute to increased breast cancer risks associated with estrogen and progesterone combinations. Additionally, its regulation of the progesterone receptor identifies a novel role for cyclin D1 in ovarian hormone control of breast development and breast carcinogenesis.

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