Abstract
Tumor progression requires ablation of suppressor functions mediated by transforming growth factor β (TGFβ) signaling and by oncogene-induced senescence (OIS), but how these functions are canceled in specific subtypes of breast cancer remains unknown. In this study, we show that HER2-overexpressing breast cancer cells avert TGFβ- and OIS-mediated tumor suppression by switching expression of 2 functionally distinct isoforms of the transcription factor C/EBPβ, which has been implicated previously in breast cancer development. HER2 signaling activates the translational regulatory factor CUGBP1, which favors the production of the transcriptionally inhibitory isoform LIP over that of the active isoform LAP. LIP overexpression prevents the assembly of LAP/Smad transcriptional repressor complexes on the MYC promoter in response to TGFβ, and interferes with activation of OIS responses. Treatment of HER2-transformed mammary epithelial cells with the HER2 antibody trastuzumab reduces LIP levels, restoring these suppressor responses. Our findings reveal a novel mechanism through which HER2 silences tumor suppression in a concerted manner, contributing to the potency of this oncogene in breast cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents / pharmacology
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Blotting, Western
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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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CCAAT-Enhancer-Binding Protein-beta / genetics*
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CCAAT-Enhancer-Binding Protein-beta / metabolism
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Cell Line
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Cell Line, Tumor
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Cellular Senescence / drug effects
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Cellular Senescence / genetics
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Gene Expression Regulation, Neoplastic*
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Humans
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In Situ Hybridization, Fluorescence
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Mice
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Mice, Nude
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Phosphorylation / drug effects
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Promoter Regions, Genetic / genetics
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Protein Binding / drug effects
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Protein Biosynthesis
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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RNA Interference
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Receptor, ErbB-2 / genetics*
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Receptor, ErbB-2 / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Transforming Growth Factor beta / pharmacology
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Trastuzumab
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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CCAAT-Enhancer-Binding Protein-beta
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Protein Isoforms
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Proto-Oncogene Proteins c-myc
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Transforming Growth Factor beta
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Receptor, ErbB-2
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Proto-Oncogene Proteins c-akt
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Trastuzumab