Abstract
Protein tyrosine kinase 6 (PTK6) expression, activation, and amplification of the PTK6 gene have been reported in ERBB2/HER2-positive mammary gland cancers. To explore contributions of PTK6 to mammary gland tumorigenesis promoted by activated ERBB2, we crossed Ptk6-/- mice with the mouse mammary tumor virus-ERBB2 transgenic mouse line expressing activated ERBB2 and characterized tumor development and progression. ERBB2-induced tumorigenesis was significantly delayed and diminished in mice lacking PTK6. PTK6 expression was induced in the mammary glands of ERBB2 transgenic mice before tumor development and correlated with activation of signal transducer and activator of transcription 3 (STAT3) and increased proliferation. Disruption of PTK6 impaired STAT3 activation and proliferation. Phosphorylation of the PTK6 substrates focal adhesion kinase (FAK) and breast cancer anti-estrogen resistance 1 (BCAR1; p130CAS) was decreased in Ptk6-/- mammary gland tumors. Reduced numbers of metastases were detected in the lungs of Ptk6-/- mice expressing activated ERBB2, compared with wild-type ERBB2 transgenic mice. PTK6 activation was detected at the edges of ERBB2-positive tumors. These data support roles for PTK6 in both ERBB2-induced mammary gland tumor initiation and metastasis, and identify STAT3, FAK, and BCAR1 as physiologically relevant PTK6 substrates in breast cancer. Including PTK6 inhibitors as part of a treatment regimen could have distinct benefits in ERBB2/HER2-positive breast cancers.
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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Animals
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Carcinogenesis
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Cell Proliferation
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Crk-Associated Substrate Protein / genetics
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Crk-Associated Substrate Protein / metabolism
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Crosses, Genetic
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Disease Progression
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Female
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Focal Adhesion Kinase 1 / genetics
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Focal Adhesion Kinase 1 / metabolism
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Gene Expression Regulation, Neoplastic*
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Humans
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Lung Neoplasms / genetics*
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Lung Neoplasms / metabolism
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Lung Neoplasms / secondary
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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 Neoplasms, Experimental / genetics*
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Mammary Neoplasms, Experimental / metabolism
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Mammary Neoplasms, Experimental / pathology
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Mammary Tumor Virus, Mouse / pathogenicity
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Mammary Tumor Virus, Mouse / physiology
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Mice
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Mice, Knockout
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Phosphorylation
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Protein-Tyrosine Kinases / deficiency
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Protein-Tyrosine Kinases / genetics*
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Receptor, ErbB-2 / genetics*
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Receptor, ErbB-2 / metabolism
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Retroviridae Infections / genetics*
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Retroviridae Infections / metabolism
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Retroviridae Infections / pathology
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism
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Signal Transduction
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Tumor Virus Infections / genetics*
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Tumor Virus Infections / metabolism
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Tumor Virus Infections / pathology
Substances
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Bcar1 protein, mouse
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Crk-Associated Substrate Protein
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STAT3 Transcription Factor
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Stat3 protein, mouse
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Erbb2 protein, mouse
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Protein-Tyrosine Kinases
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Receptor, ErbB-2
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Focal Adhesion Kinase 1
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Ptk2 protein, mouse
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Ptk6 protein, mouse