The role of the glucocorticoid receptor (GR) in inhibiting chemotherapy-induced apoptosis in high-grade serous ovarian carcinoma (HGS-OvCa).

Abstract

11101 Background: Ovarian cancer is the leading cause of death from gynecologic malignancies. High-grade serous ovarian cancer (HGS-OvCa) is often initially sensitive to platinum-based therapy, but relapse rates remain high. The TCGA recently found that HGS-OvCas have a gene expression and mutational profile similar to that of triple negative breast cancer (TNBC). Previously, our group demonstrated that dexamethasone treatment decreased chemotherapy-induced tumor cell apoptosis in TNBC and HGS-OvCa cell lines. We have also shown that glucocorticoid receptor (GR) activation induces expression of anti-apoptotic genes SGK1 and MKP1/DUSP1 in both HGS-OvCa and TNBC cell lines and in primary human ovarian and TNBC tumors. Methods: We examined glucocorticoid receptor (GR), estrogen receptor (ER), and progesterone receptor (PR) expression in a panel of HGS-OvCa cell lines by Western analysis and qRT-PCR. We also performed apoptosis assays with and without mifepristone, glucocorticoid and/or chemotherapy treatment using IncuCyte live-cell imaging technology in order to measure the effect of GR modulation of chemotherapy sensitivity. Results: HGS-OvCa cell lines (including CAOV3, HeyA8, SKOV3, Monty-1) all had detectable GR expression; HeyA8, SKOV3, and Monty-1 cell lines expressed very low levels of ER-alpha while all other HGS-OvCa cell lines did not express any detectable ER-alpha. Furthermore, none of the HGS-OvCa cell lines tested expressed PR.Apoptosis assays revealed that GR activation significantly inhibited gemcitabine/carboplatin-induced apoptosis in HGS-OvCa cell lines and that mifepristone could reverse this cell survival effect, presumably through GR antagonism. Conclusions: These results suggest that treatment with mifepristone, a GR antagonist, reverses GR-mediated cell survival signaling in HGS-OvCa and increases chemotherapy-induced tumor cell death. To further investigate the role of GR activity in HGS-OvCa, we are currently performing xenograft experiments with chemotherapy +/- mifepristone treatment.