Breast cancer is a complex disease with both environmental and genetic factors contributing to an individual's risk of developing disease. Heritable mutations in TP53 have been associated with Li-Fraumeni syndrome in which breast cancer is the most common tumor. Mouse models of Li-Fraumeni syndrome also exhibit frequent mammary tumors, but depend on the genetic background. The difference in incidence of mammary tumors between BM-Blc-Trp53 +/- mice (susceptible) and C57BU6-Trp5y'~ mice (resistant) has allowed us to investigate genetic mechanisms that modify susceptibility to mammary tumors. We have demonstrated that both recessive-acting and dominant-acting susceptibility alleles contribute to mammary tumor susceptibility. A recessive-acting locus that acts as a suppressor of mammary tumors (SuprMaml) has been mapped to a 10 Mb region of mouse chromosome 7. In contrast, a recombination pathway mediated loss of heterozygosity at Trp53 in mammary tumors and was inherited as a dominant trait. Therefore, BALB/c alleles appear to interfere with rates or fidelity of homology-directed repair of DMA double strand breaks. These observations provide a means to identify genes and pathways that influence susceptibility to mammary tumors in mice.
Specific Aim 1 : Analysis of the effect of Dmbtl in suppression of mammary tumors.
Aim 1. 1: The effects of Dmbtl as a tumor suppressor gene will be examined. Expression constructs will be introduced into mammary epithelial cell lines and changes in tumor incidence will be monitored.
Aim 1. 2: Expression of DMBT1 protein in normal human breast tissues and tumors will be determined to assess the value of DMBT1 as a biomarker.
Specific Aim 2 : Genetic dissection of the effects of the SuprMaml locus on incidence of mammary tumors.
Aim 2. 1: The magnitude of the tumor suppressive effect of the SuprMaml locus on incidence of mammary tumors will be determined using in congenic mice.
Aim 2. 2: The interval will be subdivided in separate congenic mice to refine the location of the tumor suppressor activity.
Specific Aim 3 : Analysis of dominant-acting modifiers that alter rates of repair of DNA double strand breaks. Genetic background may influence susceptibility to mammary tumors by altering the rates or fidelity of DNA repair. Therefore, rates of DNA double strand break repair will be monitored using synthetic substrates. Identification of genes that modify susceptibility to mammary tumors will provide markers for risk assessment and novel targets for therapeutic intervention.
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