Abstract 2967: Metformin selectively targets tumor initiating cells in erbb-2 overexpressing breast cancer models

Abstract

Abstract Metformin is an oral biguanide used for type II diabetes. Epidemiologic studies suggest a link between metformin use and reduced risk of breast and other types of cancers. erbB-2 expressing breast cancer is a subgroup of tumors with poor prognosis. Previous studies demonstrated that metformin is a potent inhibitor of erbB-2 overexpressing breast cancer cells; metformin treatment extends the life span and impedes mammary tumor development in ErbB-2 transgenic mice in vivo. However, the mechanisms of metformin associated anti-tumor activity, especially in prevention models, remain unclear. In this study, we investigated the mechanisms of metformin associated prevention/inhibition of ErbB-2 mediated breast cancer development by focusing on the potential effect of metformin on tumor initiating cells (TICs)/cancer stem cells (CSCs) in the MMTV-erbB-2 transgenic mouse model and its context with existing in vitro models. We report here for the first time that systemic administration of metformin (250 mg/kg/day, ip, between 8- and 18-week of age) selectively inhibits CD61high/CD49fhigh subpopulation, a group of TICs of MMTV-ErbB-2 mammary tumors, in preneoplastic mammary glands. Metformin also inhibited CD61high/CD49fhigh subpopulation in MMTV-erbB-2 tumor-derived cells, which was correlated with their compromised tumor initiation/development in a syngeneic tumor graft model. Molecular analysis indicated that metformin induced downregulation of erbB-2 and EGFR expression and inhibited the phosphorylation of erbB family members, IGF1R, Akt, mTOR and Stat3 in vivo. In vitro data indicate that low doses (1 mM) of metformin inhibited the self-renewal/proliferation of CSCs/TICs in ErbB-2-overexpressing breast cancer cells. We further demonstrated that the expression and activation of ErbB-2 were preferentially increased in CSC/TIC-enriched tumorsphere cells, which promoted their self-renewal/proliferation and rendered them more sensitive to metformin. Our results, especially the in vivo data, provide fundamental support for developing metformin-mediated preventive strategies targeting erbB-2-associated carcinogenesis. Citation Format: Pei Zhu, Meghan Davis, Amanda Blackwelder, Nora Bachman, Bolin Liu, Susan Edgerton, Leonard L. Williams, Ann D. Thor, Xiaohe Yang. Metformin selectively targets tumor initiating cells in erbb-2 overexpressing breast cancer models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2967. doi:10.1158/1538-7445.AM2014-2967