Breast cancer is a multigenic disease. The etiology of this disease has at minimum a 30% genetic component. Much of this genetic etiology is driven by Iow-penetrance, high-frequency modifier genes. The goal of this project is to begin to identify and characterize such modifier genes. A strategy using rat mammary cancer models to help define the complexity of this genetic etiology and identify breast cancer susceptibility genes is proposed. Specifically, this project focuses on the mammary cancer resistant WKy rat strain in which five loci controlling mammary cancer have been genetically identified. Two of these loci, Mcs5, a resistance modifier, and Mcs7, an increased susceptibility locus, will be the focus of this project. For both Mcs5 and Mcs7, recombinant congenic rats will be bred (with the WKy allele transferred to the WF background) so that each Mcs locus (sub-locus) interval is below 2 cM. Genes within this interval will be identified and characterized for gene expression and sequence differences between WKy and WF rats. Congenic rats will be used to characterize these loci by determining: a) their cell autonomy status, b) their associated mammary histopathology, c) their effects on mammary gene expression, and d) their susceptibility to other carcinogens and oncogenes. In addition, the validity of candidate genes within the minimal congenic region will be evaluated using transgenic rats. The Mcs7 QTL locus is also associated with allelic imbalance (AI) as is its human homologous region in breast cancers. It will be determined whether the same gene(s) is driving both the QTL and the AI. The discovery and characterization of at least two to three genes within these two QTLs are expected. In the future, the knowledge generated in this proposed project can be used to translate to women by asking if similarly-acting homologous alleles exist in women using a SNP-based breast cancer case-control association study.
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