Accelerated mammary tumor development in mutant polyomavirus middle T transgenic mice expressing elevated levels of either the Shc or Grb2 adapter protein

The Grb2 and Shc adapter proteins play critical roles in coupling activated growth factor receptors to several cellular signaling pathways. To assess the role of these molecules in mammary epithelial development and tumorigen esis,,ve have generated transgenic mice which individually express the Grb2 and Shc proteins in the mammary epithelium. Although mammary epithelial ce ll-specific expression of Grb2 or Shc accelerated ductal morphogenesis, mam mary tumors were rarely observed in these strains. To explore the potential role of these adapter proteins in mammary tumorigenesis, mice coexpressing either Shc or Grb2 and a mutant form of polyomavirus middle T (PyV mT) ant igen in the mammary epithelium were generated. Coexpression of either Shc o r Grb2 with the mutant PyV mT antigen resulted in a dramatic acceleration o f mammary tumorigenesis compared to parental mutant PyV mT strain. The incr eased rate of tumor formation observed in these mice was correlated,vith ac tivation of the epidermal growth factor receptor family and mitogen-activat ed protein kinase pathway. These observations suggest that elevated levels of the Grb2 or Shc adapter protein can accelerate mammary tumor progression by sensitizing the mammary epithelial cell to growth factor receptor signa ling.