Estrogen Receptor Alpha Mediates Progestin-Induced Mammary Tumor Growth by Interacting with Progesterone Receptors at the Cyclin D1/MYC Promoters

Abstract

Synthetic progesterone used in contraception drugs (progestins) can promote breast cancer growth, but the mechanisms involved are unknown. Moreover, it remains unclear whether cytoplasmic interactions between the progesterone receptor (PR) and estrogen receptor alpha (ERa) are required for PR activation. In this study, we used a murine progestin-dependent tumor to investigate the role of ERa in progestin-induced tumor cell proliferation. We found that treatment with the progestin medroxyprogesterone acetate (MPA) induced the expression and activation of ERa, as well as rapid nuclear colocalization of activated ERa with PR. Treatment with the pure antiestrogen fulvestrant to block ERa disrupted the interaction of ERa and PR in vitro and induced the regression of MPA-dependent tumor growth in vivo. ERa blockade also prevented an MPA-induced increase in CYCLIN D1 (CCND1) and MYC expression. Chromatin immunoprecipitation studies showed that MPA triggered binding of ERa and PR to the CCND1 and MYC promoters. Interestingly, blockade or RNAi-mediated silencing of ERa inhibited ERa, but not PR binding to both regulatory sequences, indicating that an interaction between ERa and PR at these sites is necessary for MPA-induced gene expression and cell proliferation. We confirmed that nuclear colocalization of both receptors also occurred in human breast cancer samples. Together, our findings argued that ERa-PR association on target gene promoters is essential for progestin-induced cell proliferation. Cancer Res; 72(9); 2416-27. Ó2012 AACR.

Modifications to glucocorticoid and progesterone receptors alter cell fate in breast cancer

“…In an MPA-dependent murine mammary tumor model, inhibition of ER with fulvestrant inhibited PR-dependent tumor formation. Guilianeli and his colleagues confirmed earlier studies that ER and PR interact and colocalize (Migliaccio et al 1998, Giulianelli et al 2012, but extended ER/PR cross talk studies with regard to the regulation of gene expression in human breast cancer cell lines and mouse tumors. Both receptors were detected (via ChIP assays) at the promoters of CCND1 and MYC genes in T47D cells.…”

“…Significantly, ER and PR interact in both rapid signaling (Razandi et al 2003, Boonyaratanakornkit et al 2007) and transcriptional contexts (Ballare et al 2003, Giulianelli et al 2012, Daniel et al 2015, Mohammed et al 2015. Indeed, cross talk between ER and PR appears to be extensive (Migliaccio et al 1998) and clearly impacts global gene expression and breast cancer cell fate (Giulianelli et al 2012, Daniel et al 2015, Mohammed et al 2015, Need et al 2015 (further discussed later). For example, classic studies demonstrated that in the presence of progestin, ER augments PR-dependent gene expression and tumor growth.…”

“…These receptors have recently been shown to interact as part of novel transcription complexes that function to promote endocrine therapy resistance (De Amicis et al 2010, Ciupek et al 2015, Daniel et al 2015. In addition to ER:AR transcriptional complexes (Rechoum et al 2014), GR:AR (reviewed in Narayanan et al 2015) and ER:PR (Giulianelli et al 2012, Daniel et al 2015, Mohammed et al 2015 cooperation also occur in breast and prostate cancer models. For example, PR is emerging as an important modifier of luminal (ER+) breast cancer development and progression, acting in part via novel ER/PR/PELP1 signaling and transcriptional complexes (Daniel et al 2015).…”

Progesterone/RANKL Is a Major Regulatory Axis in the Human Breast

“…Hormonally ablated mice and rats differ from endocrine-intact animals, which might more closely reflect the patients analyzed in the present study. Hormone signaling is extremely context-dependent, and there is increasing evidence for interactions between ER and PR at the molecular level that may account for this phenomenon (39).…”

Upregulation of ATBF1 by progesterone-PR signaling and its functional implication in mammary epithelial cells

“…In addition, there appears to be an autoregulatory negative feedback loop between ATBF1 and estrogen-ER signaling, as the transcription of ATBF1 is increased by estrogen-ER while ATBF1 protein is degraded by the estrogen-responsive ubiquitin E3 ligase EFP [15,16]. PR is a well known target gene of estrogen-ER signaling [17], and ERa mediates progestin-induced tumor growth by interacting with PR [18]. We therefore examined whether ATBF1 is also involved in the function of Pg-PR signaling in mammary epithelial cells.…”