Journal
CANCER CELL
Volume 19, Issue 1, Pages 86-100Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2010.10.035
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Funding
- NIH [RO1 CA109311]
- Breast SPORE [CA116199]
- CCSG [CA16672]
- DOD [COE W81WXH-06-2-0033]
- (NSC, Taiwan) [NSC-96-3111-B]
- Cancer Center of Excellence, Taiwan [DOH99-TD-C-111-005]
- National Breast Cancer Foundation, Inc.
- Kadoorie Charitable Foundation
- Breast Cancer Research Foundation
- M. D. Anderson-China Medical University and Hospital
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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-beta-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.
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