Crosstalk between progesterone receptor membrane component 1 and estrogen receptor α promotes breast cancer cell proliferation

Progesterone (P4) and estradiol (E2) have been shown to stimulate and regulate breast cancer proliferation via classical nuclear receptor signaling through progesterone receptor (PR) and estrogen receptor alpha (ER alpha), respectively. However, the basis of communication between PR/ER alpha and membrane receptors remains largely unknown. Here, we aim to identify classical and nonclassical endocrine signaling mechanisms that can alter cell proliferation through a possible crosstalk between PR, ER alpha, and progesterone receptor membrane component 1 (PGRMC1), a membrane receptor frequently observed in breast cancer cells. While P4 and E2 treatment increased cell proliferation of ER+/PR+/PGRMC1 overexpressing breast cancer cells, silencing ER alpha and PR or treatment with selective estrogen receptor modulator (SERM) tamoxifen, or (PR-antagonist) RU-486 decreased cell proliferation. All four treatments rapidly altered PGRMC1 mRNA levels and protein expression. Furthermore, P4 and E2 treatments rapidly activated EGFR a known interacting partner of PGRMC1 and its downstream signaling. Interestingly, downregulation of ER alpha by tamoxifen and ER alpha silencing decreased the expression levels of PGRMC1 with no repercussions to PR expression. Strikingly PGRMC1 silencing decreased ER alpha expression irrespective of PR. METABRIC and TCGA datasets further demonstrated that PGRMC1 expression was comparable to that of ER alpha in Luminal A and B breast cancers. Targeting of PR, ER alpha, and PGRMC1 confirmed that a crosstalk between classical and nonclassical signaling mechanisms exists in ER+ breast cancer cells that could enhance the growth of ER+/PR+/PGRMC1 overexpressing tumors. There exists a void in understanding the communication between classical and nonclassical endocrine signaling. Although progesterone receptor membrane component 1 (PGRMC1) is able to bind to progesterone, the exact signaling mechanism remains unknown. The authors demonstrate that a classical and nonclassical endocrine signaling crosstalk between the estrogen receptor and PGRMC1 exists, and that this crosstalk may promote the growth of breast cancers.

Automated summary

The study reveals that progesterone and estradiol can promote breast cancer cell proliferation through different signaling pathways, including interaction with the membrane receptor PGRMC1. This signaling mechanism plays a critical role in the growth of ER+ breast cancer cells.