Hsp90 Inhibition Results in Glucocorticoid Receptor Degradation in Association with Increased Sensitivity to Paclitaxel in Triple-Negative Breast Cancer

Abena S. Agyeman, Wesley J. Jun, David A. Proia, Caroline R. Kim, Maxwell N. Skor, Masha Kocherginsky, Suzanne D. Conzen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Targetable molecular drivers for triple-negative breast cancer (TNBC) have been difficult to identify; therefore, standard treatment remains limited to conventional chemotherapy. Recently, new-generation small-molecule Hsp90 inhibitors (e.g., ganetespib and NVP-AUY922) have demonstrated improved safety and activity profiles over the first-generation ansamycin class. In breast cancer, clinical responses have been observed in a subset of TNBC patients following ganetespib monotherapy; however, the underlying biology of Hsp90 inhibitor treatment and tumor response is not well understood. Glucocorticoid receptor (GR) activity in TNBC is associated with chemotherapy resistance. Here, we find that treatment of TNBC cell lines with ganetespib resulted in GR degradation and decreased GR-mediated gene expression. Ganetespib-associated GR degradation also sensitized TNBC cells to paclitaxel-induced cell death both in vitro and in vivo. The beneficial effect of the Hsp90 inhibitor on paclitaxel-induced cytotoxicity was reduced when GR was depleted in TNBC cells but could be recovered with GR overexpression. These findings suggest that GR-regulated anti-apoptotic and pro-proliferative signaling networks in TNBC are disrupted by Hsp90 inhibitors, thereby sensitizing TNBC to paclitaxel-induced cell death. Thus, GR+ TNBC patients may be a subgroup of breast cancer patients who are most likely to benefit from adding an Hsp90 inhibitor to taxane therapy.

Original languageEnglish (US)
Pages (from-to)114-126
Number of pages13
JournalHormones and Cancer
Volume7
Issue number2
DOIs
StatePublished - Apr 1 2016

Funding

Synta Pharmaceuticals Corporation provided pharmaceutical-grade ganetespib but no financial support for these studies. We thank Dr. Nick Lu from Northwestern University for his helpful discussions concerning GR isoforms and Mr. Ani Solanki from the University of Chicago Animal Resource Center for his assistance with tail vein injections. We also thank Dr. Larissa Belova and Nicole Lee for initial experiments with geldanamycin and paclitaxel. This work was supported by the National Institutes of Health (NIH) [R01CA089208 (S. D. Conzen) and R21CA149472 (S. D. Conzen)], the University of Chicago’s Breast Cancer SPORE NIH P50CA125183 (O. I. Olopade, S.D. Conzen), the University of Chicago Comprehensive Cancer Center Support Grant NIH P30CA014599 (M. M. Le Beau, S. D. Conzen), and the Susan G. Komen Postdoctoral Fellowship Grant (PDF15333330, A. Agyeman).

ASJC Scopus subject areas

  • Endocrine and Autonomic Systems
  • Endocrinology
  • Oncology
  • Cancer Research
  • Endocrinology, Diabetes and Metabolism

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