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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 338–346 (2007)Cite this article

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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Figure 1: Reduced rate of tumor development, number of tumors and lung metastases in NDL2 Ptpn1−/− mice.
Figure 2: Distinct mammary gland histopathology in NDL2 Ptpn1+/+ mice compared with NDL2 Ptpn1−/− mice.
Figure 3: Reduced expression levels of ErbB2 and ErbB3 in breast tumors of NDL2 Ptpn1−/− transgenic mice.
Figure 4: Decreased Ras-MAPK signaling in breast tumors of NDL2 Ptpn1−/− mice.
Figure 5: Downregulation of Akt activation in NDL2 Ptpn1−/− transgenic mice.
Figure 6: Increased apoptosis in breast tumor samples of NDL2 Ptpn1−/− mice.
Figure 7: PTP1B inhibitor administration delays the onset of mammary tumor development in NDL2 Ptpn1+/+ mice.
Figure 8: Overexpression of PTP1B in breast induces mammary gland tumorigenesis.

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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.).

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Author notes

  1. Nadia Dubé

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

Authors and Affiliations

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

    Marilene Paquet

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

    Yongxin Han & Brian P Kennedy

  4. Molecular Oncology Group, McGill University Health Centre, Royal Victoria Hospital, Montreal, H3A 1A1, Quebec, Canada

    William J Muller

  5. Department of Biochemistry, McGill University, Montreal, H3G 1Y6, Quebec, 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.

Corresponding author

Correspondence to Michel L Tremblay.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

PTP1B deficiency impairs tumorigenesis in NDL2 mice. (PDF 462 kb)

Supplementary Fig. 2

Unaltered Src phosphorylation during mammary tumor progression in NDL2-ptpn1 null mice. (PDF 106 kb)

Supplementary Fig. 3

Administration of PTP1B inhibitor in NDL2-ptpn1+/+ normalizes glucose level. (PDF 49 kb)

Supplementary Table 1

Summary of phenotypic abnormalities in MMTV-PTP1B transgenic mice. (PDF 56 kb)

Supplementary Methods (PDF 12 kb)

Supplementary Note (PDF 96 kb)

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Julien, S., Dubé, N., Read, M. et al. Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis. Nat Genet 39, 338–346 (2007). https://doi.org/10.1038/ng1963

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