Hormone receptor signaling in estrogen receptor positive breast cancer

Estrogen receptor (ER) and progesterone receptor (PR) signaling tightly interact in controlling postnatal breast development and impinge on breast carcinogenesis. PR is a direct transcriptional target of ER signaling and ER and PR bind closely to DNA and interact physically. The clinical significance of their molecular interactions remains unclear as most studies are done using simplistic or non-physiological models. Here, we exploit intraductal xenografts of ER+ breast cancer (BC) cell lines and patient-derived tumor cells to study ER and PR signaling in physiological endocrine settings. Relative tumor growth stimulation by 17-Î²-estradiol (E2), progesterone (P4) and the combination of the two is cell line and PDX-dependent. Across all models both ER and PR are required for tumor growth. Ectopic PR expression restores growth in genetically or pharmacologically ER-ablated tumor cells and induces ER-dependent gene expression in MCF7 xenografts showing that PR mediates ER function. PR stimulates tumor growth and metastasis independent of ligand. In PDXs PR induction correlates with tumor growth. Our findings show differential hormone sensitivities of luminal BC and reveal PR as essential for hormone receptor positive tumor progression and suggest PR degradation as a therapeutic option for ER BCs.

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

Cathrin Brisken, Valentina Scabia

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 a (ER) signaling. As the PR itself is a target gene of ER, the complex interactions are experimentally difficult to dissect and still poorly understood. Ex vivo 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.

BIOSCIENTIFICA LTD2020

Progestins used for hormonal contraception in Switzerland: study of their effects on the breast epithelium

Marie Shamseddin

Breast cancer is the most commonly diagnosed cancer and the most common cause of cancer death among women. Hormones have been shown to have a key role in breast development and carcinogenesis. Repeated activation of progesterone receptor (PR) signaling as it occurs during menstrual cycles is important in cancer risk. Through hormonal contraception many women are exposed to synthetic PR agonists, progestins, either on their own or in combination with the synthetic estrogen receptor (ER) agonist, ethinyl estradiol (EE). Progestins vary in their chemical structures and biological activities. Epidemiological studies show that hormonal contraceptions increase the risk of breast cancer but to date there have been few studies that analyze specific progestins regarding the breast cancer risk they confer. We hypothesized that different progestins have distinct abilities to induce cell proliferation and to modulate gene expression in the breast epithelium and this may ultimately have different effects on breast cancer risk. To test the hypothesis that different progestins currently used in hormonal contraceptions in Switzerland have distinct abilities to induce the expression of important mediators of PR action, receptor activator of NF-ÎºB ligand (RANKL) and Wnt4, we employed mouse mammary gland organoids and human breast tissue microstructures. We find that androgenic progestins strongly induce RANKL and Wnt4 whereas anti-androgenic progestins fail to do so. To test the ability of different progestins currently used in hormonal contraceptions in Switzerland to induce cell proliferation in human breast epithelium, we humanized mouse mammary gland using intraductal injection of human breast epithelial cells obtained from reduction mammoplasty surgery. We show that breast epithelial cells maintain hormone receptor expression and remain hormone responsive in this approach. We find that the androgenic progestins, Gestodene and Levonorgestrel, promote cell proliferation over two months more than progesterone. Furthermore, we show that Androgen receptor (AR) inhibition abrogates promegestone-induced RANKL induction and reduces cell proliferation induced by androgenic progestin, LNG. We also show that activation of AR signaling through DHT exposure is sufficient to induce proliferation of human breast epithelial cells. Thus, different progestins have different biological effects on the breast epithelium that appear to be related to their androgenic activities.

EPFL2018

Progestins used for hormonal contraception in Switzerland: study of their effects on the breast epithelium

Marie Shamseddin

EPFL2018