Abstract 212: Targeting p73 as a strategy for enhancing anticancer efficiency of chemotherapeutic drugs to triple-negative human breast cancers
Weiping Yu, Richa Tiwary, Kimberly A. Kline, Bob G. Sanders · Cancer Research · 2010
Abstract Successful treatment of p53-mutant, triple-negative breast cancer (TNBC) remains a daunting challenge. Chemotherapeutic drugs such as doxorubicin (DOX) and cisplatin (CDDP) remain the first line treatments for TNBC; however, chemotherapy eventually fails due to acquired drug resistance and toxicity. Therefore, new treatments for overcoming drug resistance and toxicity in TNBC are badly needed. Here we report on the reconstitution of the p53 tumor suppressor pathway in a p53-independent manner via p53 homolog p73 as an exciting possibility for improving cancer therapy in p53 mutant breast cancers. α-TEA, a small bio-active lipid analog of vitamin E, exhibits potent anticancer actions in human breast and murine mammary cancer both in vitro and in vivo. Treatments with combinations of α-TEA plus DOX or CDDP enhances in vitro apoptotic killing of two p53-mutant TNBC cells; namely, MDA-MB-231 and BT-20 cells. Sub-apoptotic doses of α-TEA plus non-apoptotic doses of DOX or CDDP significantly enhanced caspase-8 and 9 mediated apoptosis in both cell lines. The combination treatments enhanced p73 protein expression, enhanced levels of death receptors-5 (DR5), CD95/APO-1 (Fas), pro-apoptotic Bax and Noxa proteins, and reduced pro-survival Bcl-2 protein levels, all of which are p53 regulated genes. The combination treatments induced enhanced levels of phospho-c-Ab1 and JNK, upstream mediators for p73. Furthermore, combination treatments activated Yes-associated protein (Yap), a transcriptional coactivator which has been demonstrated to interact with and to enhance p73-dependent apoptosis in response to DNA damage. Taken together, our data suggest that combination of α-TEA with clinically relevant chemotherapeutic drugs (DOX or CDDP) enhances apoptosis of MDA-MB-231 and BT-20 p53-mutant TNBC cells via p73, and that c-Abl/JNK and Yap may contribute to the enhanced anti-cancer efficacy of the combination treatments. These data provide the rationale for conducting pre-clinic TNBC xenograft studies testing the safety and efficacy of this new therapeutic approach. Supported by DOD concept grant W81XWH-09-1-0564 (Yu). 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 212.