Abstract B32: The role of the glucocorticoid receptor (GR) in inhibiting chemotherapy-induced apoptosis in high-grade serous ovarian carcinoma (HGS-OvCa)

Abstract

Abstract Background: Ovarian cancer is the leading cause of death from gynecologic malignancies in developed countries. 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 evaluated GR target genes SGK1, MKP1/ DUSP1, and GILZ to determine if there is a difference in expression of the anti-apoptotic genes when exposed to glucocorticoids versus glucocorticoid antagonist. 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 in chemotherapy sensitivity. In addition, we examined human tissue microarrays of various subtypes of epithelial ovarian carcinoma using immunohistochemical stain (IHC) to examine the tumors for ER, PR, and GR expression. 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. Similar findings of GR and PR expression were also demonstrated in the primary ovarian cancer tissue microarrays. Known GR target genes SGK1, MKP1, and GILZ were upregulated in the presence of the glucocorticoid agonist dexamethasone and the addition of mifepristone inhibited this response. Apoptosis assays revealed that GR activation significantly inhibited carboplatin/gemcitabine-induced apoptosis in HGS-OvCa cell lines and that mifepristone could inhibit 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. This preliminary data may suggest that the glucocorticoid receptor may potentially be a good target for future therapeutics. To further investigate the role of GR activity in HGS-OvCas in vivo, we are currently performing xenograft experiments with chemotherapy +/- mifepristone treatment and exploring phase I clinical trials. Citation Format: Erica M. Stringer, Maxell N. Skor, Lei Zhao, Katja Gwin, Ernst Lengyel, Gini F. Fleming, Suzanne D. Conzen. The role of the glucocorticoid receptor (GR) in inhibiting chemotherapy-induced apoptosis in high-grade serous ovarian carcinoma (HGS-OvCa). [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B32.