Abstract
Amplification of the receptor tyrosine kinase ErbB2 is frequently observed in breast cancer. Amplification of erbB2 is also associated with multiple genomic gains and losses; however, the importance of these associated changes is largely unknown. We demonstrate that Brk, a cytoplasmic tyrosine kinase, is coamplified and coexpressed with ErbB2 in human breast cancers. ErbB2 interacts with Brk and increases its intrinsic kinase activity. Expression of Brk enhances the ErbB2-induced activation of Ras/MAPK signaling and cyclin E/cdk2 activity to induce cell proliferation of mammary 3-dimensional acini in culture. In a murine model of breast cancer, expression of Brk was found to shorten the latency of ErbB2-induced tumors by promoting cell proliferation, with no effect on protection from apoptosis. Furthermore, overexpression of Brk conferred resistance to the ability of Lapatinib, an ErbB2 kinase inhibitor, to inhibit ErbB2-induced proliferation. Thus, we identified Brk as a drug target for ErbB2-positive cancers.
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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Biopsy
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Breast Neoplasms / etiology
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Breast Neoplasms / genetics
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Breast Neoplasms / pathology*
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Cell Line, Tumor
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Cell Proliferation*
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Cyclin-Dependent Kinase 2 / analysis
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Cyclin-Dependent Kinase 2 / metabolism
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Female
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Gene Amplification / physiology*
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Gene Expression Profiling
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Humans
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Mammary Neoplasms, Experimental / etiology
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / pathology*
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Mice
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Neoplasm Proteins / analysis
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Neoplasm Proteins / genetics*
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Neoplasm Proteins / physiology
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Protein-Tyrosine Kinases / analysis
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / physiology*
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Receptor, ErbB-2 / analysis
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / physiology*
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src-Family Kinases / genetics
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src-Family Kinases / physiology*
Substances
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Neoplasm Proteins
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Protein-Tyrosine Kinases
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Receptor, ErbB-2
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PTK6 protein, human
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Ptk6 protein, mouse
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src-Family Kinases
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CDK2 protein, human
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Cyclin-Dependent Kinase 2