PGRMC1 promotes progestin-dependent progression of breast cancer cells by activating signaling pathways facilitating ERα activation

Background Combined menopausal hormone therapy is associated with increased breast cancer risk in postmenopausal women. In previous studies, progesterone receptor membrane component 1 (PGRMC1) was shown to play a role in the signaling of progestins, resulting in enhanced proliferation of breast cancer cells. Further investigation of PGRMC1 signaling is of high importance to better understand the effects of progestins on breast cancer risk.

Methods Upon treatment with different progestins proliferation of MCF7 overexpressing PGRMC1 cells and its phosphorylation at serine 181 were analyzed by MTT assay and western blot analysis, respectively. Co-immunoprecipitation and proximity ligation assay were used to analyze interaction of PGRMC1 with prohibitins 1 and 2 upon progestin-binding. The significance of ERα association with prohibitins and its crosstalk with TFF1 upon treatment with different progestins were investigated.

Results PGRMC1 phosphorylation status correlated to breast cancer cell proliferation upon treatment with proliferation-promoting progestins. Increased interaction between PGRMC1 and PHB1 and PHB2, respectively, was detected exclusively after treatment with proliferation-promoting progestins, which was also consistent with PGRMC1-S181 phosphorylation. Analysis of activation of TFF1 revealed facilitated ERα activation and downstream signaling dependent on PGRMC1 overexpression in hormone receptor-positive breast cancer cells.

Conclusion The results showed a functional connection between PGRMC1 Ser181 phosphorylation which is potentially modulating ERα signaling through interaction with PHB1 and PHB2 upon treatment with progestins. The subsequent activation of the ERα signaling by progestins treatment could contribute to breast cancer progression. Therefore, PGRMC1 might represent an important factor in breast cancer pathophysiology, and a target for therapeutic approaches.

Publication History

Article published online:
01 June 2021