title: Mammary epithelial-specific disruption of c-Src impairs cell cycle progression and tumorigenesis.
abstract: The tyrosine kinase c-Src is activated in a large proportion of breast cancers, in which it is thought to play a key role in promoting the malignant phenotype. c-Src activity is also elevated in transgenic mouse models of breast cancer, including the widely used polyomavirus middle-T antigen (PyVmT) model, which provides an opportunity to study the importance of c-Src in mammary tumorigenesis. However, germline c-Src deletion in mammary epithelial and stromal compartments complicates the interpretation of in vivo tumorigenesis studies as a result of severe defects in mammary gland development. We have therefore engineered a mouse strain in which deletion of c-Src can be targeted to the mammary epithelium. We demonstrate that mammary epithelial disruption of c-Src impairs proliferation and tumor progression driven by PyVmT in vivo. Whereas related kinases substitute for c-Src in PyVmT signaling, c-Src ablation impairs cell cycle progression with decreased cyclin expression and elevated expression of cyclin-dependent kinase inhibitors. Our data indicate that c-Src has essential and unique functions in proliferation and tumor progression in this mouse model that may also be important in certain contexts in some human breast cancers.
authors.affiliation: Goodman Cancer Research Center and Department of Biology,  McGill University, Montreal, QC,  Canada H3A 1A3.
authors.forename: Richard
authors.initials: R
authors.lastname: Marcotte
authors.forename: Harvey W
authors.initials: HW
authors.lastname: Smith
authors.forename: Virginie
authors.initials: V
authors.lastname: Sanguin-Gendreau
authors.forename: Rosalie V
authors.initials: RV
authors.lastname: McDonough
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D002448:Cell Adhesion; D002453:Cell Cycle; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D018450:Disease Progression; D004848:Epithelium / Q000201:enzymology* / Q000473:pathology*; D005260:Female; D017353:Gene Deletion; D020868:Gene Silencing; D006801:Humans; D008321:Mammary Glands, Animal / Q000201:enzymology* / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009928:Organ Specificity; D010766:Phosphorylation; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000952:Antigens, Polyomavirus Transforming; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D016213:Cyclins; D019061:src-Family Kinases