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

doi:10.1128/MCB.21.5.1540-1551.2001

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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^, 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, correlatingwith a poor clinical prognosis. We have previously demonstratedthat four (Y1144 Y1201, Y1227 and Y1253) of the five known Neuautophosphorylation sites can independently mediate transformingsignals. The transforming potential of two of these mutants correlateswith their capacity to recruit Grb2 directly to Y1144 (YB) orindirectly through Shc to Y1227 (YD). Here, we demonstrate thatthese transformation-competent neu mutants activate extracellularsignal-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 geneticantagonist of Ras, the transforming potential of YC was resistantto inhibition by Rap1A. To further address the significance ofthese ErbB-2-coupled signaling molecules in induction of mammarycancers, transgenic mice expressing mutant Neu receptors lackingthe known autophosphorylation sites (NYPD) or those coupled directlyto either Grb2 (YB) or Shc (YD) adapter molecules were derived.In contrast to the NYPD strains, which developed focal mammarytumors after a long latency period with low penetrance, all femalemice derived from YB and YD strains rapidly developed mammarytumors. Although female mice from several independent YB or YDlines developed mammary tumors, the YB strains developed lungmetastases at substantially higher rates than the YD strains.These observations argue that Grb2 and Shc play important anddistinct roles in ErbB-2/Neu-induced mammary tumorigenesis andmetastasis.

^* Corresponding author. Mailing address: The Institute for Molecular Biology and Biotechnology, McMaster University, 1280 MainSt. 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.

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

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