Abstract
Activation of the epidermal growth factor receptor (EGFR) family is thought to play an important role in mammary tumorigenesis and metastasis. The potent transforming activity of the EGFR family is due to their ability to heterodimerize with each other in response to a number of mitogenic ligands. The formation of EGFR and ErbB-2 heterodimers has been recently implicated as an important factor in the induction of sporadic human breast cancers. To directly assess whether the catalytic activity of EGFR is required for ErbB-2 induction of mammary tumors, we have interbred transgenic mice expressing ErbB-2 oncogene under the transcriptional control of the mouse mammary tumor virus (MMTV) promoter/enhancer to a naturally occurring mouse mutant carrying a catalytically impaired EGFR (waved-2 mice). Although the female transgenic mice possessing mutant EGFR developed mammary tumors, the tumors occurred only after a delayed latency period, and were fewer in number. The impaired tumor phenotype was further correlated with debilitated phosphorylation of the Gab1 multisubstrate adapter. These observations provide evidence that efficient ErbB-2-induced mammary tumor progression requires EGFR-dependent activation of Gab1.
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Acknowledgements
We wish to thank Dinsdale Gooden and Alison Gordon for oligonucleotide synthesis, and Brian Allore and Lilie DeSousa for automated DNA sequence analysis (MOBIX Central Facility, McMaster University). We are also grateful to Monica Graham, Carrie Merola and Judy Walls for technical support. This work was supported by grants awarded to WJM by the Canadian Breast Cancer Research Initiative. WJM is a recipient of a CRC Chair in Molecular Oncology award. AS is supported by NSERC PGS-1 award. NS is supported by a scholarship from the United States Army Medical Research Breast Cancer Research Program.
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Gillgrass, A., Cardiff, R., Sharan, N. et al. Epidermal growth factor receptor-dependent activation of Gab1 is involved in ErbB-2-mediated mammary tumor progression. Oncogene 22, 9151–9155 (2003). https://doi.org/10.1038/sj.onc.1206983
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DOI: https://doi.org/10.1038/sj.onc.1206983
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