Abstract 2622: CIP2A mediates the apoptotic effect of bortezomib on triple negative breast cancer cells

Abstract

Abstract Background: Triple negative breast cancer (TNBC) is with aggressive behaviors and poor prognosis because of the absence of a specific target for the tumor, such as in endocrine therapy and anti-HER2 therapy. Bortezomib, a proteasome inhibitor, may exert potential efficacy in TNBC through its multiple cellular effects. Our previous study has shown that CIP2A, cancerous inhibitor of PP2A, mediates effects of bortezomib on phospho-Akt (P-Akt) and apoptosis in hepatocellular carcinoma. (Oncogene, 2010). Here, we tested efficacy of bortezomib to TNBC and examined the drug mechanism. Methods: Triple negative breast cancer cell lines were used for in vitro studies. Apoptosis was examined by both flow cytometry and Western blot. Signal transduction pathways in cells were assessed by Western Blot. Gene silencing was done by small interference RNA (siRNA). In vivo efficacy of bortezomib was tested in nude mice with breast cancer xenografts. Results: Bortezomib induced apoptosis in association with down-regulation of CIP2A and P-Akt in a dose- and time-dependent manner in three TNBC cells lines (HCC-1937, MDA MB-468, MDA MB-231) but not in hormone positive MCF-7 cells. Over-expression of CIP2A in MDA MB-231 cells protected cells from bortezomib-induced apoptosis, and down-regulation of CIP2A by siRNA overcame the apoptotic resistance to bortezomib in MCF-7 cells. These data indicate that inhibiton of CIP2A determined the sensitivity of bortezomib to breast cancer cells. Importantly, bortezomib showed in vivo efficacy in HCC-1937 xenografted tumor. Conclusions: CIP2A mediates bortezomib-induced apoptosis in TNBC. Targeting CIP2A-PP2A-P-Akt signaling pathway is a novel approach for the treatment of TNBC. Supported by VGHTPE 100DHA0100591 and V99C1-059. 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 2622. doi:10.1158/1538-7445.AM2011-2622