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Heat Shock Protein 90 Inhibitors: New Mode of Therapy to Overcome Endocrine Resistance

Graduate School of Biological Sciences and Division of Tumor Cell Biology, Beckman Research Institute of City of Hope, Duarte, California

Requests for reprints: Shiuan Chen, Graduate School of Biological Sciences and Division of Tumor Cell Biology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010. Phone: 626-256-4673, ext. 63454; Fax: 626-301-8972; E-mail: schen{at}coh.org.

Aromatase inhibitors are important drugs to treat estrogen receptor (ER)–positive postmenopausal breast cancer patients. However, development of resistance to aromatase inhibitors has been observed. We examined whether the heat shock protein 90 (HSP90) inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) can inhibit the growth of aromatase inhibitor–resistant breast cancers and the mechanisms by which 17-DMAG affects proliferation. Aromatase inhibitor–responsive MCF-7aro and aromatase inhibitor–resistant LTEDaro breast epithelial cells were used in this study. We observed that 17-DMAG inhibited proliferation in both MCF-7aro and LTEDaro cells in a dose-dependent manner. 17-DMAG induced apoptosis and G₂ cell cycle arrest in both cell lines. Although inhibition of HSP90 decreased the levels of ER, the ER transcriptional activity was not affected when cells were treated with 17-DMAG together with estradiol. Moreover, detailed mechanistic studies suggested that 17-DMAG inhibits cell growth via degradation of HSP90 client proteins AKT and HER2. Collectively, results from this study provide data to support that HSP90 inhibitors may be an effective therapy to treat aromatase inhibitor–resistant breast cancers and that improved efficacy can be achieved by combined use of a HSP90 inhibitor and an AKT inhibitor. [Cancer Res 2009;69(22):8670–7]

Key Words: HSP90 inhibitors • 17-DMAG • aromatase inhibitors • breast cancer