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P53 levels determine outcome during β-catenin tumor initiation and metastasis in the mammary gland and male germ cells

Oncogene volume 25, pages 3518–3527 (2006)Cite this article

Abstract

β-catenin, an oncogene, and P53, a tumor suppressor, are common targets of mutation in human cancers. It has been observed that P53 is often inactivated in tumors involving β-catenin activation. In an attempt to model this situation in vivo, we crossed the previously characterized MMTV-ΔN-β-catenin mouse with the P53 knockout mouse. Female multiparous mice that carry the MMTV-ΔN-β-catenin transgene and that are heterozygous for P53 (TgΔN-βCat/+, P53+/−) display an increased tumor burden (2.05 vs 1.31 tumors/animal), with a generally more advanced pathology, and increased metastatic rate (39 vs 0%) relative to transgenic female mice that are wild type for P53 (TgΔN-βCat/+, P53+/+). These differences were not due to complete loss of P53 as only one of 21 tumors demonstrated loss of heterozygosity at the P53 locus. Furthermore, no mutations were present in tumors retaining a single wild-type allele. TgΔN-βCat/+, P53−/− male mice developed testicular teratomas and survived an average of 65 days, whereas non-TgΔN-βCat, P53−/− males survived an average of 84 days. Sixty-two percent of TgΔN-βCat, P53−/− mice developed testicular teratomas, whereas only 10% of the non-TgΔN-βCat, P53−/− mice developed these tumors. These results indicate that the level of P53 and the tissue of origin are important factors in determining outcome of cancer caused by oncogene activation.

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Acknowledgements

We thank Dr Lorelei Mucci for helpful discussions and advice related to our statistical analysis. We thank Dr Roderick Bronson for his technical expertise, helpful discussions and advice related to the pathology of the tumors. We would also like to thank Drs Jeff Ecsedy and Stuart Martin for critically reading the manuscript.

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  1. Department of Genetics, Harvard Medical School, Boston, MA, USA

    A G Ridgeway, J McMenamin & P Leder

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  1. A G Ridgeway
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  2. J McMenamin
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  3. P Leder
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Correspondence to P Leder.

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Ridgeway, A., McMenamin, J. & Leder, P. P53 levels determine outcome during β-catenin tumor initiation and metastasis in the mammary gland and male germ cells. Oncogene 25, 3518–3527 (2006). https://doi.org/10.1038/sj.onc.1209391

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