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

Research output: Contribution to journalArticlepeer-review

345 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 (US)
Pages (from-to)86-100
Number of pages15
JournalCancer cell
Volume19
Issue number1
DOIs
StatePublished - Jan 18 2011

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

MD Anderson CCSG core facilities

  • Advanced Technology Genomics Core
  • Flow Cytometry and Cellular Imaging Facility
  • Research Animal Support Facility

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