PGRMC1 Promotes Progestin-Dependent Proliferation of Breast Cancer Cells by Binding Prohibitins Resulting in Activation of ERα Signaling

Abstract

In previous studies, we reported that progesterone receptor membrane component 1 (PGRMC1) is implicated in progestin signaling and possibly associated with increased breast cancer risk upon combined hormone replacement therapy. To gain mechanistic insight, we searched for potential PGRMC1 interaction partners upon progestin treatment by co-immunoprecipitation and mass spectrometry. The interactions with the identified partners were further characterized with respect to PGRMC1 phosphorylation status and with emphasis on the crosstalk between PGRMC1 and estrogen receptor α (ERα). We report that PGRMC1 overexpression resulted in increased proliferation of hormone receptor positive breast cancer cell lines upon treatment with a subgroup of progestins including norethisterone and dydrogesterone that promote PGRMC1-phosphorylation on S181. The ERα modulators prohibitin-1 (PHB1) and prohibitin-2 (PHB2) interact with PGRMC1 in dependency on S181-phosphorylation upon treatment with the same progestins. Moreover, increased interaction between PGRMC1 and PHBs correlated with decreased binding of PHBs to ERα and subsequent ERα activation. Inhibition of either PGRMC1 or ERα abolished this effect. In summary, we provide strong evidence that activated PGRMC1 associates with PHBs, competitively removing them from ERα, which then can develop its transcriptional activities on target genes. This study emphasizes the role of PGRMC1 in a key breast cancer signaling pathway which may provide a new avenue to target hormone-dependent breast cancer.

Quo vadis PGRMC? Grand-Scale Biology in Human Health and Disease

“…PGRMC1 interaction with prohibitins may also affect that checkpoint. By mass spectrometric identification of proteins present in co-immunoprecipitation co-IP pellets with PGRMC1, we identified prohibitins in co-IP pellets from MIA PaCa-2 pancreatic cancer cells [37], and MCF-7 and T47D ESRα/PGR positive breast cancer cells [349]. In the breast cancer cells PHB1 and PHB2 were both associated with PGRMC1 after treatment with the progestogens NET or dydrogesterone.…”

“…In MIA PaCa-2 cells PGRMC1 is present in the same protein complexes as both PHBs and alphaactinin (although direct protein-protein interactions have not been demonstrated) [37]. PHBs are also recruited into PGRMC1 protein complexes by progestogen treatment of estrogen receptor alpha (ESRα)/PGR-positive breast cancer cells [349].…”

Insights on the Role of PGRMC1 in Mitotic and Meiotic Cell Division

“…Under these circumstances, the most informative studies are those in which PGRMC1 expression is experimentally altered ( Table 1 ). Notably, all of the studies cited in Table 1 directly measured cell proliferation, either by assessing mitotic/meiotic progression, the fold increase in cell number, and the tumor mass or by using the MTT assay, previously validated by cell counting [ 103 , 104 , 105 ].…”

“…On the other hand, fewer studies have tested the hypothesis that the exogenous overexpression of PGRMC1 accelerates cell proliferation. In these studies, various breast cancer cell lines overexpressing PGRMC1 showed increased cell proliferation in response to various progestin treatments [ 103 , 104 , 105 ]. Importantly, PGRMC1 overexpression showed different outcomes that were both cell- and progestin-type-dependent.…”

Testicular Hypoplasia with Normal Fertility in Neudesin-Knockout Mice

“…20) Furthermore, PGRMC1 might be involved in estrogen signaling, as it promotes the estrogen-dependent proliferation of breast cancer cells. 21,22) Although whether the Cyt-b5 domain of neudesin has a binding activity to progesterone or any other steroid hormones remains unknown, the studies referred above suggest that neudesin modulates steroid hormone activities.…”