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Hint1 is a haplo-insufficient tumor suppressor in mice

Oncogene volume 25, pages 713–721 (2006)Cite this article

Abstract

The HINT1 protein, a member of the histidine triad (HIT) family, is highly conserved in diverse species and ubiquitously expressed in mammalian tissues. However, its precise function in mammalian cells is not known. As a result of its structural similarity to the tumor-suppressor protein FHIT, we used homozygous-deleted Hint1 mice to study its role in tumorigenesis. We discovered that after 2 to 3 years of age the spontaneous tumor incidence in Hint1 −/− mice was significantly greater than that in wild-type Hint1 +/+ mice (P<0.05). Using a well-established mouse model of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis we found a marked and significant (P<0.05) increase in the incidence of mammary and ovarian tumors in both, Hint1 −/− and +/− mice versus +/+ mice. The Hint1 −/− and +/− mice had similar tumor incidence and similar tumor histologies. Therefore, deletion of Hint1 in mice enhances both spontaneous tumor development and susceptibility to tumor induction by DMBA. In addition, since the Hint1 +/− tumors retained expression of the unmutated wild-type allele, Hint1 is haplo-insufficient with respect to tumor suppression in this model system.

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Acknowledgements

We thank MM Mansukhani and H Hibshoosh, Department of Pathology, Columbia University, for valuable advice on the histological studies, and CW Rumsey and A Herron, Institute of Comparative Medicine, Columbia University, for histopathological verification. We are also grateful to members of the Weinstein laboratory for critical comments on the manuscript. This research was supported by National Cancer Institute Grant CA26056-24, the TJ Martell Foundation, and the National Foundation for Cancer Research (to IB Weinstein), and National Cancer Institute Grants ES05116 and P30ES09089 (to RM Santella).

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Authors and Affiliations

  1. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA

    H Li, Y Zhang, T Su, R M Santella & I B Weinstein

  2. Institute of Human Nutrition, Columbia University, New York, NY, USA

    H Li & I B Weinstein

  3. Department of Environmental Health Science, Columbia University, New York, NY, USA

    R M Santella & I B Weinstein

  4. Department of Medicine, Columbia University, New York, NY, USA

    I B Weinstein

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  1. H Li
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Correspondence to I B Weinstein.

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Li, H., Zhang, Y., Su, T. et al. Hint1 is a haplo-insufficient tumor suppressor in mice. Oncogene 25, 713–721 (2006). https://doi.org/10.1038/sj.onc.1209111

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