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Molecular and Cellular Biology, March 2001, p. 1540-1551, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1540-1551.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Grb2 and Shc Adapter Proteins Play Distinct Roles in Neu (ErbB-2)-Induced Mammary Tumorigenesis: Implications for Human Breast Cancer

David Dankort,1,2,dagger Bart Maslikowski,1 Neil Warner,1 Nubufumi Kanno,3 Harold Kim,4 Zhixiang Wang,5 Michael F. Moran,6 Robert G. Oshima,3 Robert D. Cardiff,6 and William J. Muller1,4,7,*

Departments of Biology,1 Pathology and Molecular Medicine,7 and Medical Sciences,4 Institute for Molecular Biology and Biotechnology, McMaster University, Hamilton, Ontario, Canada L8S 4K1; Center for Comparative Medicine, University of California, Davis, Davis, California 956162; The Burnham Institute, La Jolla, California, 920373; Department of Anatomy, University of Alberta, Edmonton, Alberta, Canada T6G 2M75; and Banting and Best Department of Research and Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada M5G 1L66

Received 28 July 2000/Returned for modification 13 September 2000/Accepted 1 December 2000

Amplification of the Neu (ErbB-2 or HER-2) receptor tyrosine kinase occurs in 20 to 30% of human mammary carcinomas, correlating with a poor clinical prognosis. We have previously demonstrated that four (Y1144 Y1201, Y1227 and Y1253) of the five known Neu autophosphorylation sites can independently mediate transforming signals. The transforming potential of two of these mutants correlates with their capacity to recruit Grb2 directly to Y1144 (YB) or indirectly through Shc to Y1227 (YD). Here, we demonstrate that these transformation-competent neu mutants activate extracellular signal-regulated kinases and stimulate Ets-2-dependent transcription. Although the transforming potential of three of these mutants (YB, YD, and YE) was susceptible to inhibition by Rap1A, a genetic antagonist of Ras, the transforming potential of YC was resistant to inhibition by Rap1A. To further address the significance of these ErbB-2-coupled signaling molecules in induction of mammary cancers, transgenic mice expressing mutant Neu receptors lacking the known autophosphorylation sites (NYPD) or those coupled directly to either Grb2 (YB) or Shc (YD) adapter molecules were derived. In contrast to the NYPD strains, which developed focal mammary tumors after a long latency period with low penetrance, all female mice derived from YB and YD strains rapidly developed mammary tumors. Although female mice from several independent YB or YD lines developed mammary tumors, the YB strains developed lung metastases at substantially higher rates than the YD strains. These observations argue that Grb2 and Shc play important and distinct roles in ErbB-2/Neu-induced mammary tumorigenesis and metastasis.

* Corresponding author. Mailing address: The Institute for Molecular Biology and Biotechnology, McMaster University, 1280 Main St. West, LSB 327, Hamilton, Ontario, Canada L8S 4K2. Phone: (905) 525-9140, ext. 27306. Fax: (905) 521-2955. E-mail: mullerw{at}mcmail.cis.mcmaster.ca.

dagger Present address: Cancer Research Institute, University of California, San Francisco, San Francisco, CA 94143-0128.

Molecular and Cellular Biology, March 2001, p. 1540-1551, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1540-1551.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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