EZH2 Promotes Expansion of Breast Tumor Initiating Cells through Activation of RAF1-β-Catenin Signaling

• Published in: Cancer cell Vol. 19; no. 1; pp. 86 - 100
• Main Authors: Chang, Chun-Ju, Yang, Jer-Yen, Xia, Weiya, Chen, Chun-Te, Xie, Xiaoming, Chao, Chi-Hong, Woodward, Wendy A., Hsu, Jung-Mao, Hortobagyi, Gabriel N., Hung, Mien-Chie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.01.2011
• Subjects: Animals; Benzenesulfonates - pharmacology; Benzimidazoles - pharmacology; Benzimidazoles - therapeutic use; beta Catenin - metabolism; Breast Neoplasms - diagnosis; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Hypoxia - physiology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell Survival - physiology; Centrosome - pathology; Chromosome Aberrations; DNA Breaks, Double-Stranded; DNA Damage - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enhancer of Zeste Homolog 2 Protein; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Gene Expression - drug effects; Gene Expression - genetics; Gene Expression Regulation, Neoplastic - physiology; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Models, Biological; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Niacinamide - analogs & derivatives; Phenylurea Compounds; Phosphorylation - drug effects; Polycomb Repressive Complex 2; Proto-Oncogene Proteins c-raf - genetics; Proto-Oncogene Proteins c-raf - metabolism; Pyridines - pharmacology; Rad51 Recombinase - genetics; Rad51 Recombinase - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Sorafenib; Spheroids, Cellular - drug effects; Spheroids, Cellular - pathology; Transcription Factors - genetics; Transcription Factors - metabolism; Transplantation, Heterologous - pathology; Xenograft Model Antitumor Assays
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccr.2010.10.035

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. ► Increased EZH2 expression in BTICs enhances BTIC survival and proliferation ► EZH2-amplified RAF1-β-catenin signaling promotes BTIC expansion ► Hypoxic microenvironment promotes BTICs through upregulating EZH2 expression ► AZD6244 suppresses BTICs by inhibiting activated RAF1-ERK-β-catenin signaling