title: Role of SRC kinases in Neu-induced tumorigenesis: challenging the paradigm using Csk homologous kinase transgenic mice.
abstract: Amplification of the HER-2/neu (ErbB2) gene is observed in approximately 30% of human breast cancers, correlating with a poor clinical prognosis. Src kinases are also involved in the etiology of breast cancer, and their activation was suggested to be necessary for Neu-induced oncogenesis. To address whether Src activity is essential for Neu-mediated tumorigenesis, we used a physiologic inhibitor of Src kinase activity, the Csk homologous kinase (CHK), expressed as a mammary tissue-specific transgene. Our data, using a physiologic inhibitor of Src activity (CHK), showed that blocking of Neu-induced Src activity without altering Src expression levels had no significant effects on Neu-mediated mammary tumorigenesis in vivo. This contradicts the current paradigm that activation of Src kinases is essential for Neu-induced oncogenesis. This study is the first to distinguish between the kinase-dependent and kinase-independent actions of Src and shows that its kinase-dependent properties are not requisite for Neu-induced tumorigenesis.
authors.affiliation: Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Wellman Laboratory of Photomedicine, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Rafal
authors.initials: R
authors.lastname: Kaminski
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Zagozdzon
authors.forename: Yigong
authors.initials: Y
authors.lastname: Fu
authors.forename: Pawel
authors.initials: P
authors.lastname: Mroz
authors.forename: Wei
authors.initials: W
authors.lastname: Fu
authors.forename: Seyha
authors.initials: S
authors.lastname: Seng
authors.forename: Shalom
authors.initials: S
authors.lastname: Avraham
authors.forename: Hava Karsenty
authors.initials: HK
authors.lastname: Avraham
mesh_terms: D000818:Animals; D005260:Female; D018734:Genes, erbB-2 / Q000502:physiology; D008321:Mammary Glands, Animal / Q000201:enzymology* / Q000254:growth & development; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; C498709:Pag1 protein, mouse; D010750:Phosphoproteins; D019061:src-Family Kinases