title: Loss of PTPN12 Stimulates Progression of ErbB2-Dependent Breast Cancer by Enhancing Cell Survival, Migration, and Epithelial-to-Mesenchymal Transition.
abstract: PTPN12 is a cytoplasmic protein tyrosine phosphatase (PTP) reported to be a tumor suppressor in breast cancer, through its capacity to dephosphorylate oncogenic receptor protein tyrosine kinases (PTKs), such as ErbB2. However, the precise molecular and cellular impact of PTPN12 deficiency in breast cancer progression remains to be fully clarified. Here, we addressed this issue by examining the effect of PTPN12 deficiency on breast cancer progression in vivo, in a mouse model of ErbB2-dependent breast cancer using a conditional PTPN12-deficient mouse. Our studies showed that lack of PTPN12 in breast epithelial cells accelerated breast cancer development and lung metastases in vivo. PTPN12-deficient breast cancer cells displayed enhanced tyrosine phosphorylation of the adaptor Cas, the adaptor paxillin, and the kinase Pyk2. They exhibited no detectable increase in ErbB2 tyrosine phosphorylation. PTPN12-deficient cells were more resistant to anoikis and had augmented migratory and invasive properties. Enhanced migration was corrected by inhibiting Pyk2. PTPN12-deficient breast cancer cells also acquired partial features of epithelial-to-mesenchymal transition (EMT), a feature of more aggressive forms of breast cancer. Hence, loss of PTPN12 promoted tumor progression in a mouse model of breast cancer, supporting the notion that PTPN12 is a tumor suppressor in human breast cancer. This function was related to the ability of PTPN12 to suppress cell survival, migration, invasiveness, and EMT and to inhibit tyrosine phosphorylation of Cas, Pyk2, and paxillin. These findings enhance our understanding of the role and mechanism of action of PTPN12 in the control of breast cancer progression.
authors.affiliation: Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Montréal, Québec, Canada.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Montréal, Québec, Canada.
authors.forename: Dominique
authors.initials: D
authors.lastname: Davidson
authors.affiliation: Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Montréal, Québec, Canada.
authors.forename: Cleiton
authors.initials: C
authors.lastname: Martins Souza
authors.affiliation: Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Montréal, Québec, Canada.
authors.forename: Ming-Chao
authors.initials: MC
authors.lastname: Zhong
authors.affiliation: Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Montréal, Québec, Canada.
authors.forename: Ning
authors.initials: N
authors.lastname: Wu
authors.affiliation: Goodman Cancer Centre, McGill University, Montréal, Québec, Canada Department of Biochemistry, McGill University, Montréal, Québec, Canada.
authors.forename: Morag
authors.initials: M
authors.lastname: Park
authors.affiliation: Goodman Cancer Centre, McGill University, Montréal, Québec, Canada Department of Biochemistry, McGill University, Montréal, Québec, Canada.
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.affiliation: Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Montréal, Québec, Canada Department of Medicine, McGill University, Montréal, Québec, Canada Department of Medicine, University of Montréal, Montréal, Québec, Canada andre.veillette@ircm.qc.ca.
authors.forename: André
authors.initials: A
authors.lastname: Veillette
mesh_terms: D000818:Animals; D023102:Anoikis; D001940:Breast / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D002470:Cell Survival; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology*; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12 / Q000235:genetics* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D051418:Focal Adhesion Kinase 2; D051419:Paxillin; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12; D018719:Erb-b2 Receptor Tyrosine Kinases; C524056:Erbb2 protein, mouse; C496053:Ptk2b protein, mouse; C516739:Ptpn12 protein, mouse