Abstract 1710: Expression of erbB3 upregulates Survivin via transcription-independent mechanism in erbB2-overexpressing breast cancer cells to confer Paclitaxel resistance

Abstract

Abstract The erbB2 receptor is often activated via dimerization with another erbB receptor, such as EGFR or erbB3. Studies show that co-expression of erbB3 and erbB2 is frequently observed in breast cancer; and erbB2 requires erbB3 to stimulate breast cancer cell proliferation. Increased resistance to therapeutic agents such as paclitaxel is one of the mechanisms by which erbB2 contributes to breast tumorigenesis. While several molecular mechanisms contributing to paclitaxel resistance have been proposed, a series studies demonstrate that overexpression of erbB2 inhibits paclitaxel-induced apoptosis in breast cancer cells. However, the role of erbB3 in paclitaxel resistance remains unclear. Our current studies focus on determining the role(s) of erbB3 in erbB2-mediated paclitaxel resistance in breast cancer cells. Overexpression of exogenous erbB3 via either stable or transient transfection in erbB2-overexpressing, but not EGFR-expressing, breast cancer cells significantly decreases paclitaxel-induced growth inhibition and apoptosis. Consistently, knockdown of erbB3 expression with a specific shRNA in breast cancer cells with coexpression of both erbB2 and erbB3 enhances paclitaxel-induced apoptosis evidenced by increased DNA fragmentation, PARP cleavage, and activation of caspase-3, and -8. Furthermore, while forced overexpression of erbB3 increases, specific knockdown of erbB3 decreases the protein but not mRNA expression levels of Survivin only in the erbB2-overexpressing breast cancer cells. Targeting Survivin with specific shRNA overcomes paclitaxel resistance without effect on the expression levels of either erbB2 or erbB3. Mechanistic studies indicate that the specific PI-3K, Akt, and mTOR inhibitors, but not the MEK inhibitor, not only abrogate erbB3-mediated upregulation of Survivin, but also reinforce the erbB2/erbB3-coexpressing breast cancer cells to paclitaxel-induced growth inhibition. Our studies demonstrate that heterodimerization of erbB2/erbB3 results in paclitaxel resistance in breast cancer cells via PI-3K/Akt/mTOR signaling pathway. Elevated expression of erbB3 upregulates Survivin through transcription-independent mechanism in erbB2-overexpressing cancer cells, suggesting that novel strategies targeting erbB3 or Survivin protein translation may enhance the efficacy of chemotherapeutic agents against breast cancer with erbB2-overexpressing tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1710. doi:10.1158/1538-7445.AM2011-1710