Progesterone receptor modulates ERα action in breast cancer

Abstract

Summary Progesterone receptor (PR) expression is employed as a biomarker of estrogen receptor-α (ERα) function and breast cancer prognosis. We now show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited estrogen-mediated growth of ERα+ cell line xenografts and primary ERα+ breast tumour explants and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PgR is a common feature in ERα+ breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.

Emerging functional roles of nuclear receptors in breast cancer

“…In the presence of both estrogen and progesterone, PGR was shown to be recruited to the ESR1 complex and to redirect ESR1-binding events, resulting in a gene expression profile associated with better clinical outcome (Mohammed et al 2015). However, in the presence of estrogen alone, un-liganded PGRB activated a subset of ER target genes by acting as a molecular scaffold for the formation of a transcriptional complex with ESR1 and PELP1, resulting in a more aggressive proliferative response to estrogen (Daniel et al 2015).…”

“…Further, they showed that ESR1 binding is a highly dynamic process, with distinct ESR1-binding regions observed in samples with different outcomes. This dynamic change in ESR1 action was shown to be influenced by the action of other NRs, such as PGR (Mohammed et al 2015), as well as the signaling context leading to ESR1 activation. For example, ESR1 displayed distinct genomic binding profiles depending on whether ESR1 was activated by estrogen or through the epidermal growth factor (EGF) pathway (Lupien et al 2010).…”

A patient‐derived explant (PDE) model of hormone‐dependent cancer

“…We have previously shown that PGR is not only an ERα‐target gene but is also an ERα‐associated protein that can reprogram ERα DNA binding and transcriptional responses in breast cancer and, importantly, used the PDE model to study the transcriptome and growth effects of this ERα reprogramming by PGR (Mohammed et al ., 2015; Singhal et al ., 2016). To further investigate these findings, herein we report successful ERα ChIP‐seq in ERα‐positive breast cancer PDEs cultured with E2 in the presence or absence of synthetic PGR agonist R5020.…”

“…Therefore, the heterogeneity we observed is likely representative of individual tissue microenvironments, and the PDE model provides an avenue to more accurately dissect how the tumor setting influences ERα signaling. In support of this concept, we used genomewide profiling of hormone‐treated breast cancer PDEs to capture ERα binding events and demonstrated reprogramming of ERα binding by synthetic progestin R5020, a phenomenon we recently reported using cell line models and clinical samples (Mohammed et al ., 2015; Singhal et al ., 2016). …”

Novel twists in hormone-mediated carcinogenesis

“…Developing new drugs that extinguish ER activity is the current vogue to improve treatment outcomes. Recent work (Mohammed et al 2015) supports a novel approach, whereby the activation of the progesterone receptor (PR) redirects oestrogen-stimulated ER to genomic loci associated with better disease outcomes. In that study, it was also revealed that PR loss is a common event, especially in the luminal B subtype of ER-positive disease.…”