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.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Benzenesulfonates / pharmacology
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Benzimidazoles / pharmacology
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Benzimidazoles / therapeutic use
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Breast Neoplasms / diagnosis
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology*
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Cell Hypoxia / physiology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Cell Survival / physiology
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Centrosome / pathology
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Chromosome Aberrations
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DNA Breaks, Double-Stranded
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DNA Damage / genetics
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Enhancer of Zeste Homolog 2 Protein
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Gene Expression / drug effects
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Gene Expression / genetics
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Gene Expression Regulation, Neoplastic / physiology
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Humans
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Models, Biological
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology*
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Niacinamide / analogs & derivatives
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Phenylurea Compounds
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Phosphorylation / drug effects
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Polycomb Repressive Complex 2
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Proto-Oncogene Proteins c-raf / genetics
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Proto-Oncogene Proteins c-raf / metabolism*
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Pyridines / pharmacology
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Rad51 Recombinase / genetics
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Rad51 Recombinase / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Sorafenib
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Spheroids, Cellular / drug effects
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Spheroids, Cellular / pathology
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transplantation, Heterologous / pathology
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Xenograft Model Antitumor Assays
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beta Catenin / metabolism*
Substances
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AZD 6244
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Benzenesulfonates
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Benzimidazoles
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CTNNB1 protein, human
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DNA-Binding Proteins
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Phenylurea Compounds
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Pyridines
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Transcription Factors
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beta Catenin
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Niacinamide
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Sorafenib
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EZH2 protein, human
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Enhancer of Zeste Homolog 2 Protein
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Polycomb Repressive Complex 2
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Proto-Oncogene Proteins c-raf
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Extracellular Signal-Regulated MAP Kinases
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RAD51 protein, human
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Rad51 Recombinase