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Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer

Nature Genetics volume 29, pages 418–425 (2001)Cite this article

Abstract

Inheritance of one defective BRCA2 allele predisposes humans to breast cancer. To establish a mouse model for BRCA2-associated breast cancer, we generated mouse conditional mutants with BRCA2 and/or p53 inactivated in various epithelial tissues, including mammary-gland epithelium. Although no tumors arose in mice carrying conditional Brca2 alleles, mammary and skin tumors developed frequently in females carrying conditional Brca2 and Trp53 alleles. The presence of one wildtype Brca2 allele resulted in a markedly delayed tumor formation; loss of the wildtype Brca2 allele occurred in a subset of these tumors. Our results show that inactivation of BRCA2 and of p53 combine to mediate mammary tumorigenesis, and indicate that disruption of the p53 pathway is pivotal in BRCA2-associated breast cancer.

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Figure 1: Generation and functional analysis of the Brca2 conditional mutation.
Figure 2: Generation and functional analysis of the Trp53 conditional mutation.
Figure 3: Cre recombinase activity in epithelial tissues of K14cre transgenic mice.
Figure 4: Incidence and spectrum of tumors in K14cre females carrying conditional Brca2 and Trp53 alleles.
Figure 5: Histopathology of mammary tumors from K14cre females carrying conditional Brca2 and Trp53 alleles.
Figure 6: Histopathology of skin lesions from K14cre mice carrying conditional Brca2 and Trp53 alleles.
Figure 7: Brca2 and Trp53 gene inactivation in mammary tumors.

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Acknowledgements

We thank K. Rajewsky for Cre deleter mice, P. Soriano for R26R Cre reporter–bearing mice, S. Werner for the K14 promoter construct, R. Fassler and S. O'Gorman for cre–loxP plasmids, K. van Veen-Buurman and K. van 't Wout for zygote and blastocyst injections, F. Matthesius for assistance in genotyping the mice, J. Bulthuis, K. de Goeij, D. Hoogervorst and M. Tjin-a-Koeng for histotechnical assistance, N. Bosnie, S. Greven, A. Lagro and A. Zwerver for animal care, C. Ruivenkamp for statistical analysis and A. Loonstra, H. te Riele and M. Vooijs for critically reading the manuscript. This work was supported by funding from the Dutch Cancer Society (J.J. and R.M.).

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  1. Division of Molecular Genetics and Centre of Biomedical Genetics, Netherlands Cancer Institute, CX, 1066, Amsterdam, The Netherlands

    Jos Jonkers, Ralph Meuwissen, Hanneke van der Gulden, Martin van der Valk & Anton Berns

  2. Department of Pathology, Netherlands Cancer Institute, CX, 1066, Amsterdam, The Netherlands

    Hans Peterse

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Correspondence to Anton Berns.

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Jonkers, J., Meuwissen, R., van der Gulden, H. et al. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat Genet 29, 418–425 (2001). https://doi.org/10.1038/ng747

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