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Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis

Nature Genetics volume 39, pages 338346 (2007) | Download Citation

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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.

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Acknowledgements

We thank N. Sonenberg and S. Hardy for discussions during the course of this work. We are grateful to N. Uetani and M. Narlis from the McGill Cancer Centre Developmental Histology Facility for histological and immunohistochemical protocols and helpful advice. We acknowledge the Merck Frosst Canada medicinal chemists for the gift of the inhibitor compound used in this study. N.D. is a recipient of a Canadian Institutes of Health Research doctoral award and an Alexander McFee Memorial Fellowship. W.J.M. holds a Canada Research Chair in Molecular Oncology. M.L.T. is a Chercheur National of the Fonds de Recherche en Santé du Québec. This work was supported by a Canadian Institutes of Health Research operating grant (MOP-62887) and the Jeanne and Jean-Louis Chair in Cancer Research (M.L.T.).

Author information

Author notes

    • Nadia Dubé

    Present address: Department of Physiological Chemistry, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.

Affiliations

  1. McGill Cancer Centre, McGill University, 3655 Sir William Osler Promenade, Montreal, Quebec H3G 1Y6, Canada.

    • Sofi G Julien
    • , Nadia Dubé
    • , Michelle Read
    • , Janice Penney
    •  & Michel L Tremblay
  2. Veterinary Pathology Services, McIntyre Medical Sciences Building, McGill University, 3655 Sir William Osler Promenade, Montreal, Quebec H3G 1Y6, Canada.

    • Marilene Paquet
  3. Merck Frosst Center for Therapeutic Research, Pointe-Claire, Quebec H9R 4P8, Canada.

    • Yongxin Han
    •  & Brian P Kennedy
  4. Molecular Oncology Group, McGill University Health Centre, Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada.

    • William J Muller
  5. Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.

    • Sofi G Julien
    • , William J Muller
    •  & Michel L Tremblay

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Contributions

S.G.J. performed the research, analyzed the data and wrote the manuscript. Backcrossing was performed by M.R. and J.P. Histopathology analysis was done by M.P. PTP1B inhibitor was synthesized by Y.H. and B.P.K. W.J.W. generated the ErbB2 transgenic mice. This study was designed and coordinated by S.G.J. and M.L.T. N.D. and B.P.K. contributed critical comments on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michel L Tremblay.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    PTP1B deficiency impairs tumorigenesis in NDL2 mice.

  2. 2.

    Supplementary Fig. 2

    Unaltered Src phosphorylation during mammary tumor progression in NDL2-ptpn1 null mice.

  3. 3.

    Supplementary Fig. 3

    Administration of PTP1B inhibitor in NDL2-ptpn1+/+ normalizes glucose level.

  4. 4.

    Supplementary Table 1

    Summary of phenotypic abnormalities in MMTV-PTP1B transgenic mice.

  5. 5.

    Supplementary Methods

  6. 6.

    Supplementary Note

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DOI

https://doi.org/10.1038/ng1963

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