Date on Master's Thesis/Doctoral Dissertation

5-2021

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)

Klinge, Carolyn

Committee Member

Klinge, Carolyn

Committee Member

Gregg, Ronald

Committee Member

Cummins, Timothy

Committee Member

Sanders, Mary Ann

Author's Keywords

breast cancer; MIER3; mammary carcinoma susceptibility; Mcs3

Abstract

Breast cancer genetic susceptibility is modulated by high to low penetrance risk alleles. Population frequencies of high and moderate penetrant predisposing mutations are rare and responsible for a small percentage of population cases. Most genetic variation in breast cancer susceptibility is low penetrance common variants where causal genes and risk-associated mechanisms are largely unknown. Comparative genetics uses animal models to isolate and mechanistically evaluate genetic susceptibility to human disease. Rat strains have different susceptibility phenotypes to chemical-induced carcinogenesis. Selective breeding and genetic linkage analysis using a 7,12-dimethylbenz(a)anthracene (DMBA) rat mammary carcinogenesis model have identified Mammary carcinoma susceptibilityquantitative trait loci (McsQTLs). Research completed for this dissertation focused on Mcs3 and Mcs1b QTLs. I found elevated mammary gland expression of Mcs3-nominated and established breast cancer gene p21-activated kinase (Pak1)in response to DMBA administration. This highlighted a potential role for this gene in disease initiation. Mcs3was previously mapped to a 29.4 Mb region on rat chromosome 1using WF.COP congenic lines. I developed my own congenic lines and fine mapped this locus to 7.2 Mb, discovered pleiotropic effects of Mcs3on mammary tumor multiplicity and body mass, and identified candidate breast cancer and body mass genes/variants in orthologous human regions. Rat Mcs1bmaps to 1.8 Mb on rat chromosome 2and is orthologous to human breast cancer risk locus 5q11.2. An Mcs1band 5q11.2-nominated gene is MIER family member 3 (MIER3). I used an established rat Mcs1b congenic model to study in situMier3mammary gland expression and found most expression in luminal epithelial cells. Expression of Mier3doubled upon DMBA administration and increased along a precursor-carcinoma disease progression model. Mier3expression was significantly enhanced in embryonic mammary buds, neonatal, and pubertal mammary glands, with significant drop-off at adulthood. This implicates MIER3as a breast cancer gene that may modulate disease susceptibility during early periods of female breast development. I also provide MIER3 mechanistic insight by identifying interactions of MIER3 with nuclear proteins involved in transcriptional regulation and heterochromatin formation. Thus, MIER3 may function within a novel HDAC1/2 co-repressor complex like NuRD, Sin3A, CoREST, and family member MIER1.

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