New insight on a possible mechanism of progestogens in terms of breast cancer risk.

Abstract

Progestogens influence mammary gland development and probably breast cancer tumorigenesis by regulating a broad spectrum of physiological processes. We investigated receptor membrane-initiated actions of progestogens in MCF-7 breast cancer cells overexpressing progesterone receptor membrane component 1 (PGRMC1). MCF-7 cells were stably transfected with PGRMC1 expression plasmid (MCF-7/PGRMC1-3HA) and overexpression of PGRMC1 was verified by immune fluorescent analysis and Western blot. To test the effects of progestogens on cell proliferation, MCF-7 and MCF-7/PGRMC1-3HA cells were stimulated with a membrane-impermeable progesterone: BSA-fluorescein-isothiocyanate conjugate (P4-BSA-FITC), unconjugated progesterone (P4), medroxyprogesterone acetate (MPA), norethisterone (NET) and drospirenone (DRSP). Furthermore, reverse phase protein technology was applied to identify modified downstream signaling. Progesterone did not elicit any proliferative effect on MCF-7/PGRMC1-3HA cells. By contrast, P4-BSA-FITC, DRSP, MPA and NET significantly triggered proliferation of MCF-7/PGRMC1-3HA cells, the effect being more pronounced for NET. Almost no effect of progestogens on proliferation was observed in MCF-7 cells. In MCF-7/PGRMC1-3HA cells, expression of Erk1/2 was significantly reduced by 40% compared to MCF-7 cells. Our data indicate that PGRMC1 mediates a progestogen-dependent proliferative signal in MCF-7 cells. Of significant interest is that progesterone and synthetic progestins that are used for hormone therapy are different in their proliferative effects on MCF-7 and MCF-7/PGRMC1-3HA cells. Progesterone appears to act neutrally, whereas MPA, NET and DRSP trigger proliferation and thus might increase breast cancer risk. The data presented are very important in terms of the positive results of progestogens and breast cancer risk in clinical studies so far.