Authors:
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
Summary:
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.
Source:
Cancer Cell; Vol. 19, Issue 1, 86-100 (01/06/11)