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

Acta Obstet Gynecol Scand. 2019 Feb;98(2):250-261. doi: 10.1111/aogs.13485. Epub 2018 Nov 15.

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.

Keywords: BRCA gene; G1 phase cell-cycle checkpoints; cellular proliferation; mesenchymal stromal cells; mifepristone; ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • BRCA1 Protein / genetics*
  • BRCA2 Protein / genetics*
  • Cell Proliferation / drug effects*
  • Cell Survival / drug effects
  • Female
  • Hormone Antagonists / pharmacokinetics
  • Hormone Antagonists / pharmacology
  • Humans
  • Mesenchymal Stem Cells* / pathology
  • Mesenchymal Stem Cells* / physiology
  • Mifepristone / pharmacology*
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology
  • Ovary* / drug effects
  • Ovary* / metabolism
  • Ovary* / pathology
  • Receptors, Glucocorticoid / metabolism
  • Receptors, Progesterone / metabolism
  • Stromal Cells* / pathology
  • Stromal Cells* / physiology
  • Tumor Cells, Cultured

Substances

  • BRCA1 Protein
  • BRCA2 Protein
  • Hormone Antagonists
  • Receptors, Glucocorticoid
  • Receptors, Progesterone
  • Mifepristone

Associated data

  • GENBANK/ab126556