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, butdepends onthe geneticbackground. The differencein incidenceof mammarytumors betweenBM-Blc-Trp53*'~ mice (susceptible) and C57BU6-Trp5y'~ mice (resistant) has allowed us to investigate genetic mechanisms that modify susceptibility to mammarytumors. We havedemonstrated that bothrecessive-acting anddominant-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 inmammarytumors andwas inherited as adominant trait. Therefore, BALB/c alleles appear to interferewith rates or fidelity of homology-directed repair of DMA double strand breaks. These observations provide a means to identify genes and pathwaysthat influence susceptibility to mammary tumors in mice.
SpecificAim 1 :Analysis of the effect of Dmbtlinsuppression of mammarytumors.
Aim1. 1: The effects ofDmbtl as a tumor suppressor gene will be examined. Expression constructs will be introduced into mammary epithelial cell lines andchanges intumor incidence will bemonitored.
Aim 1. 2: Expressionof DMBT1 protein innormal 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 ofthe 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 mammarytumors byaltering the rates or fidelity of DNArepair. Therefore, rates of DNA double strand break repair will be monitored using synthetic substrates. Identificationofgenes thatmodifysusceptibilitytomammarytumors willprovidemarkers for riskassessment andnovel targets for therapeutic intervention.
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