Role of Src Kinases in Neu-Induced Tumorigenesis: Challenging the Paradigm Using Csk Homologous Kinase Transgenic Mice

Amplification of the HER-2/neu (ErbB2) gene is observed in ∼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. (Cancer Res 2006; 66(11): 5757-62)