Glucocorticoid receptor antagonism as a novel treatment for triple negative breast cancer

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 292-325-Breast & Prostate Cancer
Basic
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-312
Maxwell N. Skor*, Paul A. Volden, Abena S. Agyeman, Elizabeth A. Duckworth and Suzanne D. Conzen
The University of Chicago, Chicago, IL
The glucocorticoid receptor (GR) is a ligand-activated transcription factor that regulates genes involved in a variety of epithelial cell processes including proliferation and apoptosis. GR activation in triple-negative breast cancer (TNBC) cells initiates an anti-apoptotic gene expression profile that is associated with inhibiting chemotherapy-induced tumor cell death. In addition, meta-analyses have reported that women with early stage estrogen receptor (ER)-negative breast cancer have a significantly greater chance of relapse despite appropriate initial chemotherapy if their tumors express high levels of GR. Given the role of GR activity in chemotherapy-resistant TNBC, we tested whether co-administration of mifepristone (a GR modulator with mixed agonist/antagonist properties) would increase the effectiveness of chemotherapy in TNBC. Indeed, mifepristone administered one hour prior to paclitaxel chemotherapy decreased tumor growth in TNBC xenografts compared to treatment with paclitaxel alone. To further understand the role of GR expression and signaling in tumor progression, we expressed a doxycycline-inducible GR (NR3C1) shRNA in TNBC cell lines and evaluated the effect of GR-depletion on chemotherapy sensitivity. We found that GR-depleted cells underwent increased chemotherapy-mediated cytotoxicity compared to control shRNA-expressing cells. These findings are consistent with an important role for GR-mediated gene expression in chemotherapy resistance. Furthermore, treating GR-depleted TNBC cells with mifepristone did not augment paclitaxel-mediated cytotoxicity. To understand how mifepristone alters GR-mediated gene expression in TNBC (and reverses chemotherapy resistance), we are performing gene array experiments in mifepristone-treated cells with and without GR depletion. Our results suggest that GR modulation may be a rational approach for increasing chemotherapy effectiveness in poor-prognosis TNBC.

Pan, D., et al. (2011). "Activation of the glucocorticoid receptor is associated with poor prognosis in estrogen receptor-°©‐negative breast cancer." Cancer Res 71(20): 6360-°©‐6370. Pang, D., et al. (2006). "Dexamethasone decreases xenograft response to Paclitaxel through inhibition of tumor cell apoptosis." Cancer Biol Ther 5(8): 933-°©‐940.

Disclosure: SDC: Investigator, Patent application is pending which proposes intellectual property rights for the use of GR antagonists in ER-negative breast cancer treatment. Nothing to Disclose: MNS, PAV, ASA, EAD

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH 2 R01CA089208 and Susan G. Komen for the Cure IIR12223772