PGRMC1 is associated with ERα activation upon progestin treatment

Introduction Women receiving combined HRT are at higher risk for developing breast cancer. Progestins used in HRT have been demonstrated to stimulate PGRMC1, a protein associated with worse survival of breast cancer patients. We describe a potential mechanism by which PGRMC1 enhances cancer progression via ERα-signalling upon treatment with the progestin NET.

Methods We identified interaction partners of PGRMC1 upon NET treatment in breast cancer cell lines via Co-IP and mass spectrometry, following validation using western blotting and PLA. Enhancement of ERα-signalling was illuminated by measuring the ERα target gene Tff1 by qPCR after treatment with NET. The localization of interaction between PGRMC1, ERα and interactions partners were investigated by subcellular fractionation. Finally, the enhanced signalling resulting in modified proliferation was validated in PGRMC1 overexpressing cells after NET stimulation and fulvestrant-pre-treatment.

Results We identified the ERα-repressors PHB1 and PHB2 as interaction partners of PGRMC1 upon NET-treatment, indicating a contribution of PGRMC1 to the ERα-signalling network. Upon NET-treatment ERα translocated into the nucleus and exhibited increased activation in PGRMC1-overexpressing cell lines, mutually mediated through repression of PHBs by PGRMC1 upon NET-binding. Consequently, stimulated PGRMC1-overexpressing cell lines showed increased proliferation, whereas pre-inhibition of ERα with fulvestrant abolished this effect.

Conclusion PGRMC1 is potentially involved in ERα-signalling upon treatment with NET via interaction with PHB1 and PHB2. Subsequent ERα-signalling increases proliferation and may contribute to cancer progression. The results indicate a role of PGRMC1 in ERα-activation via inhibition of PHBs and emphasize its utility as potential prognostic factor for increased breast cancer risk.

Publication History

Article published online:
01 June 2021