Genetic mapping and mechanism of action of rat mammary carcinoma susceptibility quantitative trait locus Mcs1b.

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denDekker, Aaron D.
University of Louisville
Breast cancer susceptibility; MIER3; Mammary carcinogenesis; Mcs1b; Breast cancer susceptibility; MIER3; Mammary carcinogenesis; Mcs1b
thesis / dissertation description
Breast cancer is a complex disease that involves genetic, epigenetic, and environmental components. High and moderate penetrant genes have been identified that affect risk to developing breast cancer; however, these risk alleles are present in a small percentage of breast cancer cases. Low penetrant modifier genes have risk-associated alleles that are common in the population. Although these genes have lower penetrance, it is expected that the majority of genetic risk to developing breast cancer is controlled by common genetic variation. Studying mechanisms of common genetic variants on breast cancer risk is difficult due to their small individual effects and overlapping contribution of other risk factors; thus, animal models are commonly used. The rat mammary carcinoma susceptibility quantitative trait locus (QTL) Mcs1b was identified between mammary carcinoma-resistant Copenhagen (COP) and susceptible Wistar Furth (WF) rats on chromosome 2. This rat QTL is an ortholog of a human breast cancer-associated locus identified on human chromosome 5q; therefore, the rat Mcs1b model can be used to identify mechanisms and causative factors contributing to breast cancer risk associated with human breast cancer-associated locus 5q. The goal of the work presented in this dissertation is to identify quality candidate breast cancer risk genetic elements associated with the rat Mcs1b locus. This project utilized a well-defined rat mammary carcinogenesis system and congenic rat model to fine map and characterize the rat Mcs1b locus. My studies reduced the number of candidate genes by narrowing the rat Mcs1b locus from a 13 megabase (Mb) to a 1 Mb containing nine annotated transcripts. I determined that Mcs1b-conferred mammary carcinoma resistance is being controlled by a cell type within the mammary gland. This is an important finding because mammary carcinogenesis is dependent on both mammary gland-extrinsic and -intrinsic factors. I also found that the transcript Mier3 is differentially expressed between resistant and susceptible rat mammary glands with or without carcinogen exposure providing genetic evidence that Mier3 is a strong mammary carcinoma susceptibility gene. Taken together, these results provide insight into the mechanism by which Mier3 controls mammary carcinogenesis and implicate human MIER3 as a potential target for breast cancer prevention.