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Mdm4 loss in mice expressing a p53 hypomorph alters tumor spectrum without improving survival

Oncogene volume 33, pages 1336–1339 (2014)Cite this article

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Abstract

The p53 pathway is inactivated in most human cancers, and its reactivation in tumors appears as a promising therapeutic strategy. Overexpression of Mdm4, a p53 negative regulator, occurs in a significant fraction of human cancers. Mouse models were used to evaluate the therapeutic potential of strategies against Mdm4, and encouraging results were obtained for tumor cells in which Mdm4 overexpression prevents wild-type p53 to exert its tumor suppressive functions. However, missense mutations in the p53 gene occur in about half of human cancers, and 15% of such mutations lead to the expression of a mutant protein that retains partial activity. In this report, we used mouse models to address the therapeutic potential of strategies against Mdm4 in tumors expressing an hypomorphic p53 mutant. We found that, in an Rb+/− background promoting pituitary and thyroid tumors, decreased Mdm4 levels improved the survival of mice expressing wild-type p53, but not that of mice expressing p53ΔP, a p53 hypomorph lacking the proline-rich domain. Importantly, however, most Rb+/− p53ΔP/ΔP mice developped pituitary adenomas, but these tumors were rare in Rb+/− p53ΔP/ΔP Mdm4−/− animals, because Mdm4 loss led to increased p21 levels, a suppressor of pituitary tumor growth. On the contrary, Rb+/− p53ΔP/ΔP and Rb+/− p53ΔP/ΔP Mdm4−/− mice developped anaplastic thyroid carcinomas at equal frequencies. Importantly, wild-type p53 represses the Plk1 gene, which encodes a promising therapeutic target in anaplastic thyroid carcinomas, and this repression is improved when Mdm4 levels are decreased. On the opposite, p53ΔP is a mediocre transcriptional repressor that is not improved by Mdm4 loss. In sum, depending on the tumor type, strategies against Mdm4 that work in cells expressing wild-type p53 may not work in cells expressing an hypomorphic p53. Furthermore, p53-mediated transcriptional repression should be considered when evaluating strategies to reactivate p53 in tumors.

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Acknowledgements

We thank members of the Curie technological platforms for their contribution to this study: I Grandjean, C Daviaud and M Garcia from the Animal facility and M Richardson, M Huerre and A Nicolas from the Pathology service. We also thank L Plancke and L Charbonnier for their help with mouse dissections, and GM Wahl and M Debatisse for their support. Funding was provided from the Fondation de France (Comité Tumeurs), the Association pour la Recherche sur le Cancer, the Ligue Nationale contre le Cancer (Comité Ile de France) and the Institut National du Cancer. MF and IS received predoctoral fellowships from the Cancéropôle Ile de France, the Ministère de l’Enseignement Supérieur et de la Recherche and the Ligue Nationale Contre le Cancer.

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Authors and Affiliations

  1. Institut Curie, Centre de recherche, Genetics of Tumor Suppression, Paris, France

    M Fang, I Simeonova, B Bardot, V Lejour, S Jaber, R Bouarich-Bourimi, A Morin & F Toledo

  2. UPMC Univ Paris 06, Paris, France

    M Fang, I Simeonova, B Bardot, V Lejour, S Jaber, R Bouarich-Bourimi, A Morin & F Toledo

  3. Genetics of Tumor Suppression, CNRS UMR 3244, Paris, France

    M Fang, I Simeonova, B Bardot, V Lejour, S Jaber, R Bouarich-Bourimi, A Morin & F Toledo

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  1. M Fang
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Correspondence to F Toledo.

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Fang, M., Simeonova, I., Bardot, B. et al. Mdm4 loss in mice expressing a p53 hypomorph alters tumor spectrum without improving survival. Oncogene 33, 1336–1339 (2014). https://doi.org/10.1038/onc.2013.62

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