Open AccessMifepristone mediates anti‐proliferative effect on ovarian mesenchymal stem/stromal cells from female BRCA 1−/2− carriers
Author(s) -
PonandaiSrinivasan Sakthivignesh,
Lalitkumar Parameswaran G.,
Garcia Laura,
Varghese Suby Jo,
Carlson Joseph W.,
GemzellDanielsson Kristina,
Floter Radestad Angelique
Publication year - 2019
Publication title -
acta obstetricia et gynecologica scandinavica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.401
H-Index - 102
eISSN - 1600-0412
pISSN - 0001-6349
DOI - 10.1111/aogs.13485
Subject(s) - mifepristone , cancer research , mesenchymal stem cell , medicine , stromal cell , ovarian cancer , cell growth , apoptosis , mapk/erk pathway , endocrinology , biology , cancer , signal transduction , microbiology and biotechnology , pathology , pregnancy , biochemistry , genetics
Abstract Introduction Women with hereditary mutation in breast cancer‐associated genes ( BRCA 1−/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 BRCA 1−/2− carriers. Material and methods Ovarian BRCA 1−/2− MSC were positively selected using the markers CD 90, CD 73 and CD 105 from nine healthy women. The effect of dose response and combination treatment with mifepristone and analogs of progesterone‐ or glucocorticoid‐receptors were investigated on BRCA 1−/2− MSC in vitro using a panel of markers for proliferation ( ki67, BrdU, CDK 2, p21 CIP ), apoptosis ( BAX , BCL 2, CASPASE 3 ), tumor suppression ( TP 53, PTEN ) and cell survival ( PI 3 KCA , MAPK 3, mTOR ). Results The dose response with mifepristone treatment suggested an optimal effect with 10 μ m mifepristone, exhibiting >90% viability and significantly reducing growth signaling markers ( TP 53 and MAPK 3) . 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 , TP 53 ), and increasing the percentage of pro‐apoptotic cells. Consequently, accumulation of p21 CIP together with reduced levels of CDK 2 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 BRCA 1−/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.