Abstract
The Metadherin gene (MTDH) is prevalently amplified in breast cancer and associated with poor prognosis; however, its functional contribution to tumorigenesis is poorly understood. Using mouse models representing different subtypes of breast cancer, we demonstrated that MTDH plays a critical role in mammary tumorigenesis by regulating oncogene-induced expansion and activities of tumor-initiating cells (TICs), whereas it is largely dispensable for normal development. Mechanistically, MTDH supports the survival of mammary epithelial cells under oncogenic/stress conditions by interacting with and stabilizing Staphylococcal nuclease domain-containing 1 (SND1). Silencing MTDH or SND1 individually or disrupting their interaction compromises tumorigenenic potential of TICs in vivo. This functional significance of MTDH-SND1 interaction is further supported by clinical analysis of human breast cancer samples.
Copyright © 2014 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
MeSH terms
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9,10-Dimethyl-1,2-benzanthracene
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Animals
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Breast Neoplasms / chemically induced
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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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Breast Neoplasms / virology
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Cell Adhesion Molecules / metabolism*
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Cell Line, Tumor
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Cell Proliferation*
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Cell Transformation, Neoplastic / pathology
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Cell Transformation, Viral
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Endonucleases
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Female
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Gene Expression Regulation, Neoplastic
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Genetic Predisposition to Disease
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HEK293 Cells
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Humans
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Mammary Glands, Animal / metabolism*
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Mammary Glands, Animal / pathology
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Mammary Glands, Animal / virology
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Mammary Tumor Virus, Mouse / genetics
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Mammary Tumor Virus, Mouse / pathogenicity
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Medroxyprogesterone Acetate
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Neoplasm Invasiveness
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Neoplastic Stem Cells / metabolism*
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Neoplastic Stem Cells / pathology
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Phenotype
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Protein Binding
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RNA Interference
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RNA-Binding Proteins
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Time Factors
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Transfection
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Tumor Cells, Cultured
Substances
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Cell Adhesion Molecules
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MTDH protein, human
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Membrane Proteins
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Mtdh protein, mouse
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Nuclear Proteins
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RNA-Binding Proteins
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9,10-Dimethyl-1,2-benzanthracene
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Medroxyprogesterone Acetate
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Endonucleases
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SND1 protein, human
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Snd1 protein, mouse