Mifepristone mediates anti-proliferative effect on ovarian mesenchymal stem/stromal cells from female BRCA1−/2− carriers

Abstract

Introduction: Women with hereditary mutation in breast cancer-associated genes (BRCA1−/2−) have a higher lifetime risk of developing ovarian cancer. Here, we aimed to investigate the effect of mifepristone, a selective progesterone receptor modulator of ovarian mesenchymal stem/stromal cells (MSC) from BRCA1−/2− carriers. Material and methods: Ovarian BRCA1−/2− MSC were positively selected using the markers CD90, CD73 and CD105 from nine healthy women. The effect of dose response and combination treatment with mifepristone and analogs of progesterone- or glucocorticoid-receptors were investigated on BRCA1−/2− MSC in vitro using a panel of markers for proliferation (ki67, BrdU, CDK2, p21CIP), apoptosis (BAX, BCL2, CASPASE3), tumor suppression (TP53, PTEN) and cell survival (PI3KCA, MAPK3, mTOR). Results: The dose response with mifepristone treatment suggested an optimal effect with 10 μm mifepristone, exhibiting >90% viability and significantly reducing growth signaling markers (TP53 and MAPK3). Furthermore, combined treatment with progesterone plus mifepristone (PG+MIFE) gave an enhanced anti-proliferative effect in comparison with hydrocortisone plus mifepristone (HC+MIFE) by significantly reducing markers of proliferation (BrdU+ and Ki67 expression) and tumor suppressors (PTEN, TP53), and increasing the percentage of pro-apoptotic cells. Consequently, accumulation of p21CIP together with reduced levels of CDK2 confirms growth inhibition by reversibly arresting cell-cycle progression at the G1-S phase, not by inducing apoptosis. Conclusions: Our study showed an anti-proliferative effect on ovarian BRCA1−/2− MSC on in vitro combined treatment with mifepristone and progesterone. These findings suggest that mifepristone or other selective progesterone receptor modulators could be developed as a preventive treatment and postpone early use of prophylactic salpingo-oophorectomy as well as reduce the risk of ovarian cancer.