Mifepristone mediates anti‐proliferative effect on ovarian mesenchymal stem/stromal cells from female BRCA^1−/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.

The Immune Cells in the Development of Oral Squamous Cell Carcinoma

“…Naïve T cells (CD45RA+/CCR7+) were decreased in the microenvironment compared to PBMC of patients while regulatory T cells (CD4+/CD25+/CD127 low and CD4+/CD39+) were elevated [117]. Notably, the immunomodulatory molecule cortisol induces the formation of stem cell-like populations in epithelial cancers [118] and glucocorticoid receptor inhibition by mifepristone mediates antiproliferative effect on ovarian mesenchymal stem cells [119]. It is possible, therefore, that cancer-derived cortisol promotes immune evasion both directly by immune suppression and indirectly by enriching CSC subpopulations.…”

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“…As a common drug used for abortion in clinical practice, mifepristone has anti-glucocorticoid activity separate from its anti-progesterone effect. The addition of mifepristone to a combination cisplatin and paclitaxel regimen can prevent the development of drug resistance in ovarian cancer cells and cervical cancer cells (Jurado et al, 2009;Gamarra-Luques et al, 2012;Ponandai-Srinivasan et al, 2019). This also suggests that the activation of the glucocorticoid signaling pathway negatively impacts gynecological cancers.…”