Date on Master's Thesis/Doctoral Dissertation

5-2016

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Biochemistry and Molecular Biology

Degree Program

Biochemistry and Molecular Biology, PhD

Committee Chair

Samuelson,David

Committee Co-Chair (if applicable)

Hein, David

Committee Member

Hein, David

Committee Member

Gregg, Ronald

Committee Member

Cheng, Alan

Committee Member

Schaner-Tooley, Christine

Author's Keywords

rat; mammary cancer susceptibility; Mcs; genetics

Abstract

Breast cancer is a complex disease affected by genetic, epigenetic and environmental factors. The genetic architecture of breast cancer comprises of high to low penetrance alleles. Although low penetrance alleles associate with a small change in an individual’s risk to breast cancer, the total number of variants present and the high population frequency attributes to a much greater population based impact compared to rare high penetrance alleles. Animal models have been used to study these low penetrance modifier alleles in breast cancer. Different rat strains vary in their susceptibility to 7,12- dimethybenzanthracene (DMBA) induced mammary carcinogenesis, with the Wistar- Furth (WF) rat being highly susceptible and the Copenhagen (Cop) strain being almost completely resistant to it. Linkage analysis performed to identify quantitative trait loci associated with DMBA induced mammary carcinoma susceptibility in the WF and Cop rats led to the identification of mammary carcinoma susceptibility loci 1-4 (Mcs1-4). This dissertation focuses on Mcs3 and Mcs1b. The Mcs3 locus was predicted across two peak marker on chromosome 1 D1Mit11 and D1Wox6. My work helped to physically confirm the Mcs3 locus and map it to a 25.8 Mb region on rat chromosome 1. The Mcs1b locus was mapped to a 1.8MB region on rat chromosome 2. denDekker et al 2012, showed that the Mcs1b locus and identified Mier3 as an Mcs1b candidate gene. My studies showed, the proportion of luminal mammary epithelial cells (MECs) was higher in Mcs1b resistant mammary epithelial cell enriched extracts (MEC extracts) compared to susceptible MEC extracts. This observation suggests that luminal MECs are potentially the target cells of DMBA induced carcinogenesis and future mechanistic studies could be conducted in luminal MECs. Expression assays on MEC extracts suggest that Mitogen-Activated Protein Kinase Kinase Kinase 1 (Map3k1), GC-Rich Promoter Binding Protein 1 (Gpbp1) and Mesoderm Induction Early Response 1, Family Member 3 alternative 5’ start site variant (Mier3-alt5P) are Mcs1b candidate genes.

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