@article{bbf4b96cda9345fa9eebf3d24cc1e150,
title = "Glucocorticoid receptor activation inhibits chemotherapy-induced cell death in high-grade serous ovarian carcinoma",
abstract = "Objectives To test the hypothesis that glucocorticoid receptor (GR) activation increases resistance to chemotherapy in high-grade serous ovarian cancer (HGS-OvCa) and that treatment with a GR antagonist will improve sensitivity to chemotherapy. Methods GR expression was assessed in OvCa cell lines by qRT-PCR and Western blot analysis and in xenografts and primary human tumors using immunohistochemistry (IHC). We also examined the effect of GR activation versus inhibition on chemotherapy-induced cytotoxicity in OvCa cell lines and in a xenograft model. Results With the exception of IGROV-1 cells, all OvCa cell lines tested had detectable GR expression by Western blot and qRT-PCR analysis. Twenty-five out of the 27 human primary HGS-OvCas examined expressed GR by IHC. No cell line expressed detectable progesterone receptor (PR) or androgen receptor (AR) by Western blot analysis. In vitro assays showed that in GR-positive HeyA8 and SKOV3 cells, dexamethasone (100 nM) treatment upregulated the pro-survival genes SGK1 and MKP1/DUSP1 and inhibited carboplatin/gemcitabine-induced cell death. Concurrent treatment with two GR antagonists, either mifepristone (100 nM) or CORT125134 (100 nM), partially reversed these effects. There was no anti-apoptotic effect of dexamethasone on chemotherapy-induced cell death in IGROV-1 cells, which did not have detectable GR protein. Mifepristone treatment alone was not cytotoxic in any cell line. HeyA8 OvCa xenograft studies demonstrated that adding mifepristone to carboplatin/gemcitabine increased tumor shrinkage by 48% compared to carboplatin/gemcitabine treatment alone (P = 0.0004). Conclusions These results suggest that GR antagonism sensitizes GR+ OvCa to chemotherapy-induced cell death through inhibition of GR-mediated cell survival pathways.",
keywords = "Chemotherapy, GR antagonist, Mifepristone, Ovarian cancer",
author = "Stringer-Reasor, {Erica M.} and Baker, {Gabrielle M.} and Skor, {Maxwell N.} and Masha Kocherginsky and Ernst Lengyel and Fleming, {Gini F.} and Conzen, {Suzanne D.}",
note = "Funding Information: We thank Drs. Robert Roe and Hazel Hunt (Corcept Therapeutics) for supplying pharmaceutical-grade mifepristone and CORT125134 and sharing their extensive expertise. We thank members of the Ernst Lengyel laboratory, especially Drs. Arniban Mitra and Hillary Kenny for assistance with OvCa xenograft modeling, and the Suzanne Conzen and Matthew Brady laboratories for valuable feedback and expertise. Terri Li and the University of Chicago Medicine Comprehensive Cancer Center's Human Tissue Resource Center (HTRC) provided essential expertise for the xenograft and human tissue microarray IHC staining. We also thank the Geoffrey Greene laboratory for the use of the Incucyte{\texttrademark}. Finally, we thank the University of Chicago Cancer Research Foundation's (UCCRF) Women's Board for supporting this project. Funding Information: E. Stringer-Reasor received support from the Conquer Cancer Foundation of ASCO YIA Award, the NIH Basic Research Training in Medical Oncology Grant (T32-CA009566), and the NIH Clinical Therapeutics Training Grant (T32-GM007019). G. Fleming and S. Conzen received research support from The University of Chicago Cancer Foundation Women's Board. S. Conzen and M. Kocherginsky are co-inventors on a patent entitled “Methods and Compositions Related to Glucocorticoid Receptor Antagonist in Breast Cancer” awarded to The University of Chicago and licensed by Corcept Therapeutics. All other authors report no conflicts of interest. Study sources that provided financial support had no involvement in study design, collection of data, analysis, or interpretation. Funding Information: The study was supported by the University of Chicago Comprehensive Cancer Center NIH support grant CA-014599 (core facilities for human tissue) and The University of Chicago Cancer Research Foundation's (UCCRF) Women's Board . E. Stringer-Reasor was also supported by the Conquer Cancer Foundation of ASCO YIA Award , the NIH Basic Research Training in Medical Oncology Grant ( T32-CA009566 ), and the NIH Clinical Therapeutics Training Grant ( T32-GM007019 ). ",
year = "2015",
month = sep,
day = "1",
doi = "10.1016/j.ygyno.2015.06.033",
language = "English (US)",
volume = "138",
pages = "656--662",
journal = "Gynecologic Oncology",
issn = "0090-8258",
publisher = "Academic Press Inc.",
number = "3",
}