| Genetic factors have been estimated to account for 30% of a woman's risk to develop breast cancer. The goal of this thesis is to use a non-biased comparative genomics approach to identify a gene or genetic element that plays a role in mammary cancer in the rat. The mammary cancer susceptibility locus Mcs5c was previously shown to decrease tumor numbers by 60% and was localized to a 4.5 Mb region of rat chromosome 5.;In this thesis, I have fine-mapped the Mcs5c locus, revealing two mammary susceptibility loci within Mcs5c: Mcs5c and Mcs5d, located to regions of 301 kb and 617 kb of rat chromosome 5 respectively. This thesis focuses on the characterization of the 301 kb Mcs5c locus. The best defined resistant Mcs5c congenic line displays a 40% decrease in average carcinoma numbers after exposure to 7,12-dimethylbenz-[a] anthracene (DMBA). Mcs5c congenic rats also exhibit a 40% decrease in average carcinoma numbers after exposure to a Her2/neu oncogene, suggesting the mammary cancer resistance of Mcs5c is not DMBA specific and that Mcs5c acts past the initiation stage of carcinogenesis. A mammary transplant analysis revealed that the effect of Mcs5c is due to a host effect.;As the 301 kb Mcs5c locus is devoid of genes, we investigated whether a genetic element in Mcs5c might be regulating the expression of genes outside the locus. One of the genes located directly outside the Mcs5c locus, Tnc, was shown to be differentially expressed in the Mcs5c congenic animals. Mcs5c congenic rats exhibit a decrease in Tnc expression in the thymus and ovary after DMBA or Her2/neu treatment, but not in the thymus and ovary of untreated animals. The expression phenotype is not seen in the mammary glands of these rats.;This thesis has revealed that Mcs5c is a non-coding locus with gene regulatory properties. Mcs5c is currently hypothesized to affect mammary carcinogenesis by long-range regulation of the extracellular matrix protein Tnc in tissues other than the mammary gland. |
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