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Molecular and Cellular Biology, December 1999, p. 8169-8179, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Accelerated Mammary Tumor Development in Mutant Polyomavirus Middle T Transgenic Mice Expressing Elevated Levels of Either the Shc or Grb2 Adapter Protein

Michael J. Rauh,1,2 Valerie Blackmore,1,3 Eran R. Andrechek,1,3 Christopher G. Tortorice,1,3 Roger Daly,4 Venus Ka-Man Lai,5 Tony Pawson,5 Robert D. Cardiff,6 Peter M. Siegel,1,3 and William J. Muller1,3,7,8,*

Institute for Molecular Biology and Biotechnology,1 Medical Sciences Program,2 and Departments of Biology,3 Biochemistry,7 and Pathology and Molecular Medicine,8 McMaster University, Hamilton, Ontario, Canada L8S 4K1; Cancer Research Program, Garvan Institute, St. Vincent's Hospital, Darlinghurst, Sydney, New South Wales 2010, Australia4; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X55; and School of Medicine, University of California at Davis, Davis, California 956166

Received 23 July 1999/Returned for modification 9 September 1999/Accepted 16 September 1999

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 tumorigenesis, we have generated transgenic mice which individually express the Grb2 and Shc proteins in the mammary epithelium. Although mammary epithelial cell-specific expression of Grb2 or Shc accelerated ductal morphogenesis, mammary 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) antigen in the mammary epithelium were generated. Coexpression of either Shc or Grb2 with the mutant PyV mT antigen resulted in a dramatic acceleration of mammary tumorigenesis compared to parental mutant PyV mT strain. The increased rate of tumor formation observed in these mice was correlated with activation of the epidermal growth factor receptor family and mitogen-activated 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 signaling.

* Corresponding author. Mailing address: Cancer Research Group, Departments of Biology, Biochemistry, and Pathology and Molecular Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario, Canada L8S 4K1. Phone: (905) 525-9140, ext. 27306. Fax: (905) 521-2955. E-mail: mullerw{at}mcmail.mcmaster.ca.

Molecular and Cellular Biology, December 1999, p. 8169-8179, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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