MAMMARY-TUMORS EXPRESSING THE NEU PROTOONCOGENE POSSESS ELEVATED C-SRC TYROSINE KINASE-ACTIVITY

Amplification and overexpression of the neu (c-erbB2) proto-oncogene h as been implicated in the pathogenesis of 20 to 30% of human breast ca ncers. Although the activation of Neu receptor tyrosine kinase appears to be a pivotal step during mammary tumorigenesis, the mechanism by w hich Neu signals cell proliferation is unclear. Molecules bearing a do main shared by the c-Src proto-oncogene (Src homology 2) are thought t o be involved in signal transduction from activated receptor tyrosine kinases such as Neu. To test whether c-Src was implicated in Neu-media ted signal transduction, we measured the activity of the c-Src tyrosin e kinase in tissue extracts from either mammary tumors or adjacent mam mary epithelium derived from transgenic mice expressing a mouse mammar y tumor virus promoter/enhancer/unactivated neu fusion gene. The Neu-i nduced mammary tumors possessed six- to eightfold-higher c-Src kinase activity than the adjacent epithelium. The increase in c-Src tyrosine kinase activity was not due to an increase in the levels of c-Src but rather was a result of the elevation of its specific activity. Moreove r, activation of c-Src was correlated with its ability to complex tyro sine-phosphorylated Neu both in vitro and in vivo. Together, these obs ervations suggest that activation of the c-Src tyrosine kinase during mammary tumorigenesis may occur through a direct interaction with acti vated Neu.