Activation of the c-Src tyrosine kinase is required for the induction of mammary tumors in transgenic mice.
Transgenic mice expressing the polyomavirus (PyV) middle T oncogene in the mammary epithelium develop multifocal mammary tumors that metastasize with high frequency. The potent transforming activity of PyV middle T antigen can, in part, be attributed to its ability to associate with 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 individual c-Src family tyrosine kinases in PyV middle T antigen-induced mammary tumorigenesis, we have crossed transgenic mice carrying the mouse mammary tumor virus (MMTV)/PyV middle T antigen fusion gene with mice bearing a disrupted c-src proto-oncogene. In contrast to the rapid tumor progression seen in the original MMTV/PyV middle T antigen strains, mice expressing the transgene in the absence of functional c-Src rarely developed mammary tumors. After long latency, these mice did eventually develop abnormal hyperplastic mammary tissue. This growth disturbance was correlated with elevated expression of the PyV middle T antigen and the activation of the PyV middle T antigen-associated c-Yes tyrosine kinase. However, transgenic mice expressing the PyV middle T antigen in the mammary epithelium of wild-type or Yes-deficient mice developed multifocal mammary tumors with comparable kinetics. Taken together, these findings suggest that c-Src tyrosine kinase activity is required for PyV middle T antigen-induced mammary tumorigenesis and also illustrate an in vivo genetic approach to the dissection of mitogenic signal transduction pathways.
Guy
C T
CT
Institute for Molecular Biology and Biotechnology, McMaster University, Hamilton, Ontario, Canada.
Muthuswamy
S K
SK
Cardiff
R D
RD
Soriano
P
P
Muller
W J
WJ
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D004789:Enzyme Activation; D008325:Mammary Neoplasms, Experimental / Q000209:etiology* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009857:Oncogenes; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051575:Proto-Oncogene Proteins c-yes; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism* / Q000502:physiology; D019061:src-Family Kinases
D000952:Antigens, Polyomavirus Transforming; D011518:Proto-Oncogene Proteins; D051575:Proto-Oncogene Proteins c-yes; D016392:Proto-Oncogene Proteins pp60(c-src); C496639:Yes1 protein, mouse; D019061:src-Family Kinases