Breast cancer is the leading cause of cancer death among women worldwide. Triple negative breast cancer (negative for estrogen-, progesterone and human epidermal growth factor receptor 2 -HER2-) is a subgroup comprising 12.5% of the patients, which have a more aggressive phenotype with a tendency for early dissemination and onset at an early age. Overexpression of IGF-1R, a transmembrane receptor tyrosine kinase involved in tumor cell motility and metastatic spread, has been associated with increased malignancy degree of numerous solid tumors including breast cancer. The large majority of triple negative breast cancers (70-80%) express IGF-1R, and this is associated with a worse prognosis. Heat shock protein 90 (HSP90) is a key component of a multichaperone complex involved in post-translational folding of several oncogenic client proteins, including IGF-1R. Disrupting IGF-1R signalling by means of HSP90 inhibition is therefore potentially of interest for treating triple negative breast cancer. The most studied HSP90 inhibitor is 17AAG. However, due to its relatively poor physiochemical properties, there is a need for HSP90 inhibitors with better pharmaceutical characteristics. In this study we explore whether the novel HSP90 inhibitor NVP-AUY922 reduces IGF-1R expression and hampers IGF-1 mediated migration in triple negative breast cancer. MDA-MB-231 cells were exposed to increasing concentrations of NVP-AUY922 (0-500 nM) and compared with 17-AAG (0-500 nM) and were analysed for IGF-1R expression by Western-blotting, flow-cytometry and immunohistochemistry. The effects on IGF-1 induced migration were established by wound-healing assays. ER-positive MCF-7 cells were used as reference model. IGF-1R expression was strongly decreased (23% compared to control) after NVP-AUY922 (200nM) treatment, whereas 17-AAG (500nM) had no effect on IGF-1R levels in MDA-MB-231 cells. Both 17-AAG and NVP-AUY922 were effective in MCF-7 cells. Immunofluorescent labelling revealed the localization of IGF-1R to actin-rich regions in the leading edge of migrating breast cancer cells, with a reduced staining intensity after NVP-AUY922 treatment. IGF-1 stimulated migration rate in both MDA-MB-231 (157%) and MCF-7 (212%) cells. In accordance with the effects of HSP90 inhibition on IGF-1R expression, NVP-AUY922 (50nM) reduced IGF-1 stimulated migration (61% compared to IGF-1 stimulated cells). 17-AAG did not affect migration of MDA-MB-231 cells. In this study we have shown that HSP90 inhibition by the novel compound NVP-AUY922 potently reduces the membrane expression levels of IGF-1R and affects IGF-1 induced migration in triple negative breast cancer cells. HSP90 inhibition could be a significant systemic treatment option for triple negative breast cancer patients via inhibition of the IGF-1R pathway.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1855.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009