Date of Award
Doctor of Philosophy (PhD)
Professor William J. Muller
Although previous studies have shown that a large proportion of human breast cancers possess elevated c-Src kinase activity its role in mammary tumorigenesis is not well defined. Polyoma virus middle T antigen is known to activate members of Src family kinases (c-Src and eYes). Indeed, mammary gland specific expression of middle T antigen in transgenic mice is known to result in induction of mammary tumors. To test the role played by c-Src and c-Yes activation in mammary tumorigenesis we interbred transgenic mice expressing the middle T antigen with mice lacking either functional c-Src or c-Yes. Mice expressing middle T antigen in the absence of functional c-Src failed to develop mammary tumors while absence of c-Yes did not have any effect. This observation suggests that activation of c-Src kinase plays an important role in mammary tumorigenesis while c-Yes is dispensable for this process.
Activation of the RTK Neu is known to play an important role in breast cancer. Since c-Src tyrosine kinases appear to play a pivotal role in mammary tumorigenesis, 1 investigated whether the Src family members are involved in Neu mediated signaling and tumorigenesis. In vitro kinase assays revealed that c-Src and c-Yes kinase activities were elevated in Neu induced mammary tumors while Fyn kinase activity was not. The increase in kinase activity correlated with the ability of c-Src and c-Yes to associate with tyrosine phosphorylated Neu in vivo. This in vivo interaction is likely due to the ability of c-Src and c-Yes SH2 domains to directly associate with phosphorylated tyrosine(s) on Neu. Although other members of erbB family also play a role in breast cancer, my results suggest that among the RTKs that are known to activate c-Src (EGFR and Neu), c-Src and c-Yes interact only with Neu and not EGFR. These observations suggest that Src family kinases are involved in Neu mediated signaling and tumorigenesis and also suggest that Neu plays a role in EGF mediated activation of c-Src.
Although both c-Src and c-Yes are activated by Neu and middle T antigen, only c-Src is required for middle T mediated tumorigenesis. Indeed c-Src associates with a novel protein, p89, in transformed epithelial cells while c-Yes does not. Future identification of p89 will enable us to understand the mechanism by which c-Src transforms mammary epithelium.
Muthuswamy, Senthil K., "Role of the Src Family Tyrosine Kinases in Mammary Tumorigenesis" (1995). Open Access Dissertations and Theses. Paper 1668.