HER2-Driven Breast Cancer: Role of the Chaperonin HSP90 in Modulating Response to Trastuzumab-Based Therapeutic Combinations

Mechanistic relationships between heat shock protein 90 (HSP90) and human epidermal growth factor receptor 2 (HER2) are complex and clinical correlations in breast cancer remain inconsistent. We investigated the role of HSP90 expression in the response of breast cancer cells to HER2-targeted treatments, by measuring cell viability/proliferation and protein expression after genetic and pharmacologic HER2/HSP90 modulation. HSP90 expression was also assessed by immunohistochemistry in a series of 72 metastatic, HER2+ breast cancer patients. In HER2+ breast cancer models (AU565, BT474, MCF7-HER2), HER2 downregulation induced HSP90 upregulation and growth inhibitory synergism between trastuzumab and docetaxel. HSP90 downregulation blunted the response to trastuzumab and docetaxel and their synergistic interactions. The addition of pertuzumab caused little additional growth inhibition, but HSP90 silencing unmasked a synergistic growth inhibitory effect with the triple combination. Conversely, HSP90 downregulation blunted the therapeutic response to trastuzumab/pertuzumab/tamoxifen or trastuzumab-emtansine. In HER2+ breast cancer patients, high HSP90 expression was associated with significant progression-free survival benefit with the triple combination, as compared with trastuzumab and chemotherapy, although the interaction test was not statistically significant. Overall, our results highlight a mechanistic role for HSP90 in determining the response of breast cancer cells to HER2-targeted agents and suggest that trastuzumab/pertuzumab combinations may be particularly advantageous in HSP90-high, HER2+ breast cancer.