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Xiaohe Yang

Xiaohe Yang

North Carolina Central University, USA

Title: Metformin targets mammary/cancer stem cells in breast cancer prevention and treatment

Biography

Xiaohe Yang completed his Ph.D. in Microbiology/Immunology from RFUMS/The Chicago Medical School and postdoctoral studies from Northwestern University. He is currently an Associate Professor of Biology at North Carolina Central University. His research focuses on erbB-2/Her-associated breast cancer etiology, prevention and therapeutics. He has published more than 50 papers in reputed journals. Dr.Yang was a recipient of the Career Development Award from the Department of Defense Breast Cancer Research Program and the AACR Minority-Serving Institution Faculty Scholar in Cancer Research Awards. He is also an American Cancer Society Research Scholar.

Abstract

Increasing evidence suggests that targeting cancer stem cells (CSCs)/tumor-initiating cells (TICs) is a promising approach to treat and prevent cancer diseases. Recent advances indicate that use of metformin, a common anti- diabetes drug, is associated with reduced risk of breast and other types of cancers. However, the mechanisms of metformin mediated anti-cancer activities remain unclear. ErbB2/Her2 amplification in breast cancer has been associated with poor prognosis and therapeutic resistance. We sought to determine the effect of metformin on CSCs/TICs in ERBB2 tumor models. Our in vitro results showed that metformin has potent anti-proliferative effects on trastuzumab-resistant breast cancer cells via inhibition of erbB2/IGF-1R interactions. Using mammary tumor virus (MMTV)-ErbB2 transgenic mouse model, we demonstrated systemic administration of metformin to these mice during the premalignant risk window selectively inhibited the CD61(high)/CD49f(high) mammary epithelial cells. Cells with this phenotype had been identified as luminal progenitor cells and may function as TICs during tumor development in MMTV-ErbB2 mice. We further demonstrated that metformin also inhibited CD61(high)/CD49f(high) subpopulation in ErbB2 tumor-derived cells in vitro and tumor development in a syngeneic tumor graft model. Mechanistic studies indicated that metformin inhibited the expression and activation of ErbB family members and IGF-1R, AKT/mTOR signaling, and STAT3, c-myc associated activities. In vitro data also showed that low doses of metformin inhibited the self-renewal/proliferation of cancer stem cells (CSCs)/TICs in ErbB2-overexpressing breast cancer cells. Our results provide fundamental support for developing metformin-mediated preventive strategies targeting ErbB2-associated carcinogenesis.