Suppressed estrogen supply extra-ovarian progesterone receptor membrane component 1 in menopause.

In post-menopausal women, intra-mammary estrogen, which is converted from extra-ovarian estrone (E1), promotes the growth of breast cancer. Since the aromatase inhibitor letrozole does not suppress 17β-estradiol (E2) production from E1, high intra-mammary E1 concentrations impair letrozole's therapeutic efficacy. Progesterone receptor membrane component 1 (Pgrmc1) is a non-classical progesterone receptor associated with breast cancer progression. In the present study, we introduced a heterozygous knockout (hetero KO) murine model exhibiting low Pgrmc1 expression, and observed estrogen levels and steroidogenic gene expression. Naïve hetero KO mice exhibited low estrogen (E2 and E1) levels and low progesterone receptor (PR) expression, compared to wild-type mice. In contrast, hetero KO mice that have been ovariectomized (OVX), including letrozole-treated OVX mice (OVX-letrozole), exhibited high estrogen levels and PR expression. Increased extra-ovarian estrogen production in hetero KO mice was observed with the induction of steroid sulfatase (STS). In MCF-7 cell, letrozole suppressed PR expression, but knockdown increased PR and STS expression. Our presented results highlight the important role of in modulating estrogen production when ovary-derived estrogen is limited, thereby suggesting a potential therapeutic approach for letrozole resistance.