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Mapping Genetic Modifiers of Mammary Tumor Susceptibility in BALB/c-p53+/- Mice

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Annual rept. 1 Sep 2000-31 Aug 2001

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The TP53 tumor suppressor gene is critical for inhibiting tumors in many tissues. Heterozygosity at TP53 has been associated with the Li-Fraumeni tumor susceptibility syndrome where breast cancer is the most common tumor in women with this syndrome. We found that the incidence of mammary tumors in mice that were heterozygous for Trp53 varied among strains. Therefore, the mammary tumor-susceptible strain BALBcMed was crossed with a resistant strain C57BL6J to create a panel of 220 backcross mice to allow genetic mapping of chromosomal intervals containing modifiers of mammary tumor susceptibility that varied between these strains. We have monitored tumor type and latency in these mice for 15 months with 50 mice remaining. The incidence of mammary tumors in the Trp53- backcross mice was considerably reduced compared to the BALBc 6O vs 30 confirming the presence of modifier loci in the BALBc strain that confer susceptibility. We are evaluating linkage of the tumor phenotype to BALBc polymorphisms in the Ink4a and Prdkc genes that result in proteins that have reduced activity in cell cycle checkpoint and DNA repair activities. We have also established the mechanism by which the wild type allele of Trp53 is lost during mammary tumor formation in these mice.

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  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

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