Lee Sang R, Yang Hyun, Jo Seong Lae, Lee Young Ho, Lee Hye Won, Park Bae-Keun, Hong Eui-Ju
College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea.
KM Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea.
J Biomed Res. 2021 Jan 29;35(3):228-237. doi: 10.7555/JBR.35.20200172.
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.
在绝经后女性中，由卵巢外雌酮（E1）转化而来的乳腺内雌激素会促进乳腺癌的生长。由于芳香化酶抑制剂来曲唑不能抑制E1转化生成17β-雌二醇（E2），乳腺内高浓度的E1会削弱来曲唑的治疗效果。孕激素受体膜成分1（Pgrmc1）是一种与乳腺癌进展相关的非经典孕激素受体。在本研究中，我们构建了一个表现为低Pgrmc1表达的杂合敲除（杂合KO）小鼠模型，并观察雌激素水平和类固醇生成基因的表达。与野生型小鼠相比，未经处理的杂合KO小鼠表现出低雌激素（E2和E1）水平以及低孕激素受体（PR）表达。相反，已接受卵巢切除术（OVX）的杂合KO小鼠，包括接受来曲唑治疗的OVX小鼠（OVX-来曲唑组），表现出高雌激素水平和PR表达。观察发现，杂合KO小鼠中卵巢外雌激素生成增加是由类固醇硫酸酯酶（STS）的诱导引起的。在MCF-7细胞中，来曲唑抑制PR表达，但敲低后PR和STS表达增加。我们展示的结果突出了Pgrmc1在卵巢来源雌激素受限情况下调节雌激素生成中的重要作用，从而提示了一种针对来曲唑耐药的潜在治疗方法。
