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

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-?-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.

SUBMITTER: Chang CJ 

PROVIDER: S-EPMC3041516 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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

Chang Chun-Ju CJ   Yang Jer-Yen JY   Xia Weiya W   Chen Chun-Te CT   Xie Xiaoming X   Chao Chi-Hong CH   Woodward Wendy A WA   Hsu Jung-Mao JM   Hortobagyi Gabriel N GN   Hung Mien-Chie MC  

Cancer cell 20110106 1

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 iden  ...[more]

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