Abstract
The C-terminal binding protein (CtBP) is a NADH-dependent transcriptional repressor that links carbohydrate metabolism to epigenetic regulation by recruiting diverse histone-modifying complexes to chromatin. Here global profiling of CtBP in breast cancer cells reveals that it drives epithelial-to-mesenchymal transition, stem cell pathways and genome instability. CtBP expression induces mesenchymal and stem cell-like features, whereas CtBP depletion or caloric restriction reverses gene repression and increases DNA repair. Multiple members of the CtBP-targeted gene network are selectively downregulated in aggressive breast cancer subtypes. Differential expression of CtBP-targeted genes predicts poor clinical outcome in breast cancer patients, and elevated levels of CtBP in patient tumours predict shorter median survival. Finally, both CtBP promoter targeting and gene repression can be reversed by small molecule inhibition. These findings define broad roles for CtBP in breast cancer biology and suggest novel chromatin-based strategies for pharmacologic and metabolic intervention in cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Alcohol Oxidoreductases / genetics*
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Alcohol Oxidoreductases / metabolism
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Binding Sites
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Breast Neoplasms / classification
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Breast Neoplasms / genetics*
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Caloric Restriction
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Cell Differentiation / drug effects
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Cell Differentiation / genetics
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Cluster Analysis
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DNA Repair / drug effects
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DNA Repair / genetics
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Down-Regulation / drug effects
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Down-Regulation / genetics
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Epithelial Cells / pathology
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Epithelial-Mesenchymal Transition / drug effects
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Epithelial-Mesenchymal Transition / genetics
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Epithelium / drug effects
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Epithelium / metabolism*
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Epithelium / pathology
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Regulatory Networks / genetics
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Genome, Human / genetics*
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Genomic Instability* / drug effects
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Glucose / pharmacology
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Humans
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MCF-7 Cells
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Neoplasm Invasiveness
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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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Prognosis
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Small Molecule Libraries / pharmacology
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Survival Analysis
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Up-Regulation / drug effects
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Up-Regulation / genetics
Substances
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DNA-Binding Proteins
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Small Molecule Libraries
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Alcohol Oxidoreductases
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C-terminal binding protein
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Glucose