90 YEARS OF PROGESTERONE: Progesterone receptor signaling in the normal breast and its implications for cancer

Abstract

<jats:p>Progesterone is considered as the pregnancy hormone and acts on many different target tissues. Progesterone receptor (PR) signaling is important for normal development and the physiologic function of the breast and impinges on breast carcinogenesis. Both systemically and locally, in the breast epithelium, there are multiple layers of complexity to progesterone action, many of which have been revealed through experiments in mice. The hormone acts via its receptor expressed in a subset of cells, the sensor cells, in the breast epithelium with different signaling outcomes in individual cells eliciting distinct cell-intrinsic and paracrine signaling involving different mediators for different intercellular interactions. PR expression itself is developmentally regulated and the biological outcome of PR signaling depends on the developmental stage of the mammary gland and the endocrine context. During both puberty and adulthood PR activates stem and progenitor cells through Wnt4-driven activation of the myoepithelium with downstream Adamts18-induced changes in extracellualr matrix (ECM) / basal membrane (BM). During estrous cycling and pregnancy, the hormone drives a major cell expansion through Rankl. At all stages, PR signaling is closely tied to estrogen receptor α (ER) signaling. As the PR itself is a target gene of ER, the complex interactions are experimentally difficult to dissect and still poorly understood. <jats:italic>Ex vivo</jats:italic> models of the human breast and studies on biopsy samples show that major signaling axes are conserved across species. New intraductal xenograft models hold promise to provide a better understanding of PR signaling in the normal breast epithelium and in breast cancer development in the near future.</jats:p>

Contraceptive progestins with androgenic properties stimulate breast epithelial cell proliferation

“…A recent side-by-side comparison of various progestins used in OCs revealed cell line-and transfection-related differences (Enfield et al, 2020) pointing to the limited value of such in vitro models for making clinical predictions and the need for better models. Indeed, little is known about the effects of different progestins on the breast epithelium because we lacked adequate models to study hormone action (Ö zdemir et al, 2018;Brisken & Scabia, 2020). Primary human breast epithelial cells (HBECs) can be readily isolated from reduction mammoplasty specimens but they lose hormone receptor (HR) expression when cultured in vitro.…”

Progesterone receptors in normal breast development and breast cancer

“…Many reviews have addressed in detail the different stages of the mammary gland (MG) development [42][43][44], and many others have focused in the role of progesterone (Pg) and PR in the normal and neoplastic MG [45][46][47][48][49][50][51][52][53]. Briefly, the MG develops after birth to generate a rudimentary duct tree.…”

“…Receptor activator of NFκB (RANKL) [64][65][66][67][68][69], WNT4 [70], calcitonin [71], amphiregulin [72], CXC chemokine receptor type 4 (CXCR4)/Stromal cell derived factor 1 (CXCL12) [73] , ID4 [74], and ADAMTS18 [75] proved to be key players mediating Pg-induced paracrine cell proliferation (reviewed in [49,76]). Not all PR+ cells produce all of these factors [77], suggesting that specialized PR+ subsets of cells may selectively respond to different stimuli or cell contexts [48]. In addition to the paracrine effect, an autocrine Pg-mediated induction of cell proliferation involves the activation of CCND1 [78].…”

90 Years of progesterone: Ninety years of progesterone: the ‘other’ ovarian hormone

“…The importance of progesterone in the female reproductive system and mammary gland development is now well-established, as contextualised in reviews by DeMayo and Lydon and by Brisken and Scabia ( Brisken & Scabia 2020 , DeMayo & Lydon 2020 ). Clinically, this understanding has led to the development of progesterone receptor modulating drugs with corresponding indications including contraception, termination of pregnancy, dysfunctional uterine bleeding and endometrial and breast cancers.…”

“…These evolving hormonal environments create significant challenges for studying the effects of PR signaling in the breast and Cathrin Brisken's team have pioneered several techniques and models to overcome these. She reviews these developments together with an overview on recognised mediators of PR signaling in normal breast physiology (Brisken & Scabia 2020).…”