title: Amplified Ras-MAPK signal states correlate with accelerated EGFR internalization, cytostasis and delayed HER2 tumor onset in Fer-deficient model systems.
abstract: The non-receptor tyrosine kinase Fer belongs to a distinct subfamily of F-BAR domain containing kinases implicated in vesicular trafficking and signaling downstream of adhesion and growth factor receptors. Targeted inactivation of the fer gene in a transgenic mouse model of HER2(+), breast cancer was associated with delayed tumor onset and reduced proliferative rates in tumor cells. Fer deficiency was associated with increased rates of epidermal growth factor (EGF)-induced epidermal growth factor receptor (EGFR) internalization and amplified Ras-Raf-Mek-Erk (Ras-MAPK) signaling in primary mammary tumor epithelial cells, as well as increased cytotoxic and anti-proliferative sensitivity to the dual EGFR/HER2 inhibitor Lapatinib (LPN). These observations suggest a model in which accelerated ligand-induced EGFR internalization in Fer-deficient cells hypersensitizes the Ras-MAPK pathway to EGF, resulting in MAPK signal amplification to levels that induce cytostasis, rather than proliferation. Thus, Ras-MAPK cytostatic signaling delays HER2 tumor initiation and increases LPN cytotoxicity in Fer-deficient model systems. Taken together, these data suggest that targeting Fer alone, or in combination with LPN, may be of therapeutic benefit in HER2(+) breast cancer.
authors.affiliation: 1] Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, Kingston, Ontario, Canada [2] Department of Pathology and Molecular Medicine, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada [3] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Sangrar
authors.affiliation: Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, Kingston, Ontario, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Shi
authors.affiliation: 1] Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, Kingston, Ontario, Canada [2] Department of Pathology and Molecular Medicine, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Mullins
authors.affiliation: 1] Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, Kingston, Ontario, Canada [2] Department of Pathology and Molecular Medicine, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
authors.forename: D
authors.initials: D
authors.lastname: LeBrun
authors.affiliation: Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Ingalls
authors.affiliation: 1] Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, Kingston, Ontario, Canada [2] Department of Pathology and Molecular Medicine, Queen's Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
authors.forename: P A
authors.initials: PA
authors.lastname: Greer
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D066246:ErbB Receptors; D020929:Mitogen-Activated Protein Kinase Kinases; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D018631:ras Proteins; C052602:proto-oncogene protein c-fes-fps; C541485:EGFR protein, mouse