The Role of the SUPRMAM1 Locus in Responses to Ionizing Radiation and Susceptibility to Mammary Tumors

THE ROLE OF THE SUPRMAM1 LOCUS IN RESPONSES TO IONIZING RADIATION AND SUSCEPTIBILITY TO MAMMARY TUMORS MAY 2011 NICHOLAS B. GRINER, B.S., UNIVERSITY OF WASHINGTON Ph.D., UNIVERSITY OF MASSACHUSETTTS, AMHERST Directed by: Professor D. Joseph Jerry Loss of p53 function 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-Trp53females, but are rare in C57BL/6-Trp53 mice. Prevalence of genomic instability appears to contribute to the phenotype as loss of heterozygosity (LOH) 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 was that BALB/c-Trp53 mice are more susceptible to mammary tumors due to impaired Homologous Recombination Repair (HRR) 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