Abstract 3730: Akt activity is suppressed by doxorubicin through downregulation of ErbB receptors and its enhanced activity is associated with higher sensitivity to doxorubicin in breast cancer

Abstract

Abstract Anthracyclines are the backbone of breast cancer therapy and benefit patients in both the adjuvant and metastatic setting whereas they are effective for 50-60% of breast cancer patients and cause substantial morbidity and occasional life-threatening toxic effects. For these reasons, it has been eagerly anticipated to develop diagnostic markers which can predict efficacy of the treatment. HER2 amplification or overexpression of its protein (HER2 positivity) has been shown to be associated with relative benefit from anthracycline-based chemotherapy (Gennari A. et al., J. Natl. Cancer Inst, 100, 14-20, 2008). However, HER2 is positive in 15-25% of breast tumor tissues and no clear biological mechanism between HER2 positivity and action of anthracyclines has been reported. In this study, we have shown that doxorubicin exerts its anti-tumor activity through inhibiting ErbBs-Akt signal pathway. Promoted activity of Akt was associated with not only HER2 but EGFR overexpression and responsiveness to doxorubicin in human breast cancer cell lines. As well as doxorubicin, PI3 kinase inhibitor caused growth inhibition and apoptosis in cells with promoted Akt activity more significantly than cells with weakly activated Akt. Doxorubicin-induced cytotoxic stress induced internalization and degradation of ErbBs followed by inactivation of Akt. This was confirmed with the observation that doxorubicin caused decrease in the amount of immunocomplex formed between HER3 and p85, PI3 kinase regulatory subunit. These data indicate that cancer cells with ErbBs overexpression and promoted Akt activity are dependent on activities of these factors for their growth and survival, and doxorubicin inhibits the ErbBs-Akt signal pathway through inducing downregulation of ErbB receptors. Furthermore, we found that highly phosphorylated Akt in tumors corresponds to improved recurrence-free survival in breast cancer patients treated with anthracycline-based adjuvant chemotherapy relative to weakly phosphorylated Akt. Taken together, we provide mechanistic insight into molecular basis of correlation between HER2 positivity and sensitivity to anthracyclines, and propose a new possibility that Akt activity is a useful predictor of response to anthracycline-based chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3730.