Role and mechanism of action of tyrosine kinases in mammary tumorigenesis

Abstract

<p>Overexpression and amplification of the neu proto-oncogene have been implicated in the development of aggressive human breast cancer. To investigate the effect of mammary gland-specific expression of the neu protooncogene, transgenic mice carrying the unactivated neu gene under the transcriptional control of the mouse mammary tumor virus (MMTV) promoter/enhancer were established. Overexpression of neu in the mammary tumors was associated with elevated Neu intrinsic tyrosine kinase activity and the stochastic development of focal mammary tumors which frequently metastasized. These observations provide the first direct evidence that expression of the proto-oncogenic form of neu results in a heritable development of metastatic mammary tumors.</p> <p>Another potent tyrosine kinase activity that has been implicated in the genesis of murine mammary tumors is that associated with polyomavirus middle T antigen (PyV MTAg). Expression of MMTV/PyV middle T antigen in the mammary glands of transgenic mice resulted in the induction of multifocal mammary tumors which frequently metastasized to the lung. The potent transforming activity of PyV MTAg can, in part, be attributed to its ability to associate with an activate a number of e-Src family tyrosine kinases (e-Src, e-Yes, and Fyn). In order to assess the role of individual members of the e-Src family of tyrosine kinases in PyV MTAg induced mammary tumorigenesis, I have crossed the MMTV/PyV middle T fusion gene with mice bearing disrupted c-src or e-yes alleles. Mice expressing the PyV middle T transgene in the absence of functional c-Src rarely developed metastatic mammary tumors. However, transgenic mice expressing the PyV MTAg in mammary epithelium lacking functional c-Yes developed multifocal mammary tumors with kinetics comparable to MMTV/PyV middle T strains possessing a functional c-Yes. These findings suggest that c-Src tyrosine kinase activity is required for PyV MTAg induced mammary tumorigenesis and also illustrate a in vivo genetic approach to dissect mitogenic signal transduction pathways.</p>