Article abstract
Nature Genetics 39, 338 - 346 (2007)
Published online: 28 January 2007 | doi:10.1038/ng1963
Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis
Sofi G Julien1,5, Nadia Dubé1,6, Michelle Read1, Janice Penney1, Marilene Paquet2, Yongxin Han3, Brian P Kennedy3, William J Muller4,5 & Michel L Tremblay1,5
Abstract
We investigated the role of protein tyrosine phosphatase 1B (PTP1B) in mammary tumorigenesis using both genetic and pharmacological approaches. It has been previously shown that transgenic mice with a deletion mutation in the region of Erbb2 encoding its extracellular domain (referred to as NDL2 mice, for 'Neu deletion in extracellular domain 2') develop mammary tumors that progress to lung metastasis. However, deletion of PTP1B activity in the NDL2 transgenic mice either by breeding with Ptpn1-deficient mice or by treatment with a specific PTP1B inhibitor results in significant mammary tumor latency and resistance to lung metastasis. In contrast, specific overexpression of PTP1B in the mammary gland leads to spontaneous breast cancer development. The regulation of ErbB2-induced mammary tumorigenesis by PTB1B occurs through the attenuation of both the MAP kinase (MAPK) and Akt pathways. This report provides a rationale for the development of PTP1B as a new therapeutic target in breast cancer.
- McGill Cancer Centre, McGill University, 3655 Sir William Osler Promenade, Montreal, Quebec H3G 1Y6, Canada.
- Veterinary Pathology Services, McIntyre Medical Sciences Building, McGill University, 3655 Sir William Osler Promenade, Montreal, Quebec H3G 1Y6, Canada.
- Merck Frosst Center for Therapeutic Research, Pointe-Claire, Quebec H9R 4P8, Canada.
- Molecular Oncology Group, McGill University Health Centre, Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada.
- Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
- Present address: Department of Physiological Chemistry, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
Correspondence to: Michel L Tremblay1,5 e-mail: michel.tremblay@mcgill.ca
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