EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-β-catenin signaling

Chun Ju Chang, Jer Yen Yang, Weiya Xia, Chun Te Chen, Xiaoming Xie, Chi-Hong Chao, Wendy A. Woodward, Jung Mao Hsu, Gabriel N. Hortobagyi, Mien Chie Hung*

*Corresponding author for this work

Research output: Contribution to journalArticle

280 Scopus citations

Abstract

It has been proposed that an aggressive secondary cancer stem cell population arises from a primary cancer stem cell population through acquisition of additional genetic mutations and drives cancer progression. Overexpression of Polycomb protein EZH2, essential in stem cell self-renewal, has been linked to breast cancer progression. However, critical mechanism linking increased EZH2 expression to BTIC (breast tumor initiating cell) regulation and cancer progression remains unclear. Here, we identify a mechanism in which EZH2 expression-mediated downregulation of DNA damage repair leads to accumulation of recurrent RAF1 gene amplification in BTICs, which activates p-ERK-β-catenin signaling to promote BTIC expansion. We further reveal that AZD6244, a clinical trial drug that inhibits RAF1-ERK signaling, could prevent breast cancer progression by eliminating BTICs.

Original languageEnglish
Pages (from-to)86-100
Number of pages15
JournalCancer Cell
Volume19
Issue number1
DOIs
StatePublished - 18 Jan 2011

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    Chang, C. J., Yang, J. Y., Xia, W., Chen, C. T., Xie, X., Chao, C-H., Woodward, W. A., Hsu, J. M., Hortobagyi, G. N., & Hung, M. C. (2011). EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-β-catenin signaling. Cancer Cell, 19(1), 86-100. https://doi.org/10.1016/j.ccr.2010.10.035