title: EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-β-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-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.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Chun-Ju
authors.initials: CJ
authors.lastname: Chang
authors.forename: Jer-Yen
authors.initials: JY
authors.lastname: Yang
authors.forename: Weiya
authors.initials: W
authors.lastname: Xia
authors.forename: Chun-Te
authors.initials: CT
authors.lastname: Chen
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Xie
authors.forename: Chi-Hong
authors.initials: CH
authors.lastname: Chao
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Woodward
authors.forename: Jung-Mao
authors.initials: JM
authors.lastname: Hsu
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D000818:Animals; D001557:Benzenesulfonates / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D018385:Centrosome / Q000473:pathology; D002869:Chromosome Aberrations; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010766:Phosphorylation / Q000187:drug effects; D063151:Polycomb Repressive Complex 2; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000077157:Sorafenib; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C517975:AZD 6244; D001557:Benzenesulfonates; D001562:Benzimidazoles; C495270:CTNNB1 protein, human; D004268:DNA-Binding Proteins; D010671:Phenylurea Compounds; D011725:Pyridines; D014157:Transcription Factors; D051176:beta Catenin; D009536:Niacinamide; D000077157:Sorafenib; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; C495153:RAD51 protein, human; D051135:Rad51 Recombinase