Heat shock protein 90 inhibitors: new mode of therapy to overcome endocrine resistance.
Aromatase inhibitors are important drugs to treat estrogen receptor alpha (ERalpha)-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 G(2) cell cycle arrest in both cell lines. Although inhibition of HSP90 decreased the levels of ERalpha, the ERalpha 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.
Graduate School of Biological Sciences and Division of Tumor Cell Biology, Beckman Research Institute of City of Hope, Duarte, California 91010, USA.
Cynthie
C
Wong
Shiuan
S
Chen
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D047072:Aromatase Inhibitors / Q000627:therapeutic use; D016227:Benzoquinones / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D047628:Estrogen Receptor alpha / Q000187:drug effects; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects
D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D016227:Benzoquinones; D047628:Estrogen Receptor alpha; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin