Epigenome Modulated Xenobiotic Metabolism Controls Breast Cancer Development and Progression in Agouti Avy/a Mice

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Biological Sciences

Date of Award

Fall 2017

Abstract

Constitutively expressed agouti signaling peptide (ASP) promotes yellow coat color and obesity in mice. Although ASP-mediated obesity factors are suggested for cancer predisposition, molecular mechanisms are unclear. Since epigenetic regulation is responsible for the phenotype differences in Agouti viable yellow (Avy) mice, we hypothesized that an altered epigenome landscape controls breast cancer (BC) development and progression in Avy/a mice. To test this hypothesis we employed the Avy mouse model. In Avy mice, differential methylation of the ASP promoter determines coat color variation. Using a randomized block design, 22 isogenic Avy/a (8 yellow, 7 mottled [mixture of yellow and brown], 7 pseudoagouti [brown]) and 8 non-agouti (a/a black) age matched mice were subjected to the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA; 30 mg/kg per mouse weight) once a week for 6 weeks to induce breast cancer. Results showed that there was no significant difference in tumor burden or tumor latency between non-agouti mice and Avy/a littermates despite being significantly more lean than their yellow (p = 0.0001) and slightly mottled (p < 0.0001) littermates. Amongst Avy/a littermates, tumor latency was significantly increased in pseudoagouti littermates compared to yellow (p = 0.0058) and slightly mottled (p = 0.0137) littermates. In addition, tumor burden was significantly decreased in pseudoagouti littermates compared to yellow (p = 0.0039) and slightly mottled (p = 0.0010) littermates. Ontology analyses of gene array data identified 11 liver-specific genes mainly involved in phase 2 UDP-glucuronosyltransferase and sulfotransferase-dependent detoxification pathways upregulated in pseudoagouti mice compared to their Avy/a littermates. In support of our ontology analyses, AhR, CYP1A1, and ASP mRNA expression in mammary tissues from all four of our treatment groups were not significantly different, suggesting that phase 1 DMBA metabolism is similar in Avy/a and non-agouti mice, and that aberrant ASP expression may not be responsible for differential BC susceptibility in Avy/a mice. Taken together, our results suggest that differential expression of genes involved in phase 2 xenobiotic detoxification pathways rather than ASP-induced obesity factors control breast cancer susceptibility in Avy/a mice.

Advisor

Venugopalan Cheriyath

Subject Categories

Biochemistry, Biophysics, and Structural Biology | Biology | Life Sciences

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