ACTIVATION OF THE C-SRC TYROSINE KINASE IS REQUIRED FOR THE INDUCTIONOF MAMMARY-TUMORS IN TRANSGENIC MICE

Transgenic mice expressing the polyomavirus (PyV) middle T oncogene in the mammary epithelium develop multifocal mammary tumors that metasta size with high frequency. The potent transforming activity of PyV midd le T antigen can, in part, be attributed to its ability to associate w ith and to activate a number of c-Src family tyrosine kinases (c-Src, c-Yes, and Fyn). As a first step toward assessing the role of individu al c-Src family tyrosine kinases in PyV middle T antigen-induced mamma ry tumorigenesis, we have crossed transgenic mice carrying the mouse m ammary tumor virus (MMTV)/PyV middle T antigen fusion gene with mice b earing a disrupted c-src proto-oncogene. In contrast to the rapid tumo r progression seen in the original MMTV/PyV middle T antigen strains, mice expressing the transgene in the absence of functional c-Src rarel y developed mammary tumors. After long latency, these mice did eventua lly develop abnormal hyperplastic mammary tissue. This growth disturba nce was correlated with elevated expression of the PyV middle T antige n and the activation of the PyV middle T antigen-associated c-Yes tyro sine kinase. However, transgenic mice expressing the PyV middle T anti gen in the mammary epithelium of wild-type or Yes-deficient mice devel oped multifocal mammary tumors with comparable kinetics. Taken togethe r, these findings suggest that c-Src tyrosine kinase activity is requi red for PyV middle T antigen-induced mammary tumorigenesis and also il lustrate an in vivo genetic approach to the dissection of mitogenic si gnal transduction pathways.