Abstract
Abstract Loss of p53 can lead to a variety of cancers, including breast cancer. Mice heterozygous for the p53 gene (designated Trp53+/−) develop spontaneous mammary tumors, but this depends on the strain background and has been linked to a locus on chromosome 7 (designated SuprMam1). Mammary tumors are common in BALB/c-Trp53+/−females, but are rare in C57BL/6-Trp53+/− mice. Prevalence of genomic instability appears to contribute to the phenotype as loss of heterozygosity (LOH) through mitotic recombination is significantly more common among tumors arising in BALB/c-Trp53+/− mice compared to C57BL/6J-Trp53+/− mice. This increased LOH in BALB/c-Trp53+/− tumors was shown to be due to recombination events. The Balb/c strain has been shown to have a deficiency in non-homologous end joining (NHEJ) of DNA double strand breaks (dsb), however, this does not account for the increase of LOH events in tumors. Our hypothesis is that BALB/c-Trp53+/− mice are more susceptible to mammary tumors due to impaired dsb repair leading to LOH. Using the COMET assay, we demonstrate that dsbs persist longer in BALB/c-Trp53+/− mouse embryonic fibroblasts (MEFs) compared to C57BL/6J-Trp53+/− MEFs. Similarly, co-localization of H2AX and the homologous recombination protein RAD51 remain at dsb longer in BALB/c-Trp53+/− MEFs compared to C57BL/6-Trp53+/− MEFs suggesting a decreased efficiency of homologous recombination. Using a GFP reporter assay, homology-directed repair was decreased by 36% in MEFs from BALB/c-Trp53+/− compared to C57BL/6-Trp53+/−. Palb2 is a candidate gene as it lies within the SuprMam1 interval and has been shown to contribute to heritable breast cancer. Although no coding SNPs were found within Palb2, preliminary results show the BALB/c-Trp53+/− cells have a 30% decrease in Palb2 RNA compared to C57BL/6-Trp53+/− cells as assayed by RT-qPCR. These results identify defects in homology-directed repair of dsb in BALB/c which are linked to susceptibility to mammary tumors in this strain. Experiments are in progress analyzing these features in congenic strains. The results will elucidate potential low penetrance modifiers that determine resistance to mammary tumors in both mice and humans which can be used as targets for therapy as well as breast cancer screening. Citation Information: Cancer Res 2009;69(23 Suppl):B56.
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