Activation of the c-Src tyrosine kinase is required for the induction of mammary tumors in transgenic mice

Chantale T. Guy, Senthil K. Muthuswamy, Robert Cardiff, Philippe Soriano, William J. Muller

Research output: Contribution to journalArticle

171 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)23-32
Number of pages10
JournalGenes and Development
Volume8
Issue number1
DOIs
StatePublished - Jan 1 1994

Keywords

  • c-Src
  • mammary tumorigenesis
  • metastasis
  • PyV middle T antigen
  • signal transduction
  • transgenic mice

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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