Epigenome modulated xenobiotic detoxification pathways control DMBA-induced breast cancer in agouti Avy/a mice

Environmental xenobiotics with genotoxic activity are carcinogenic. However, individual differences in the susceptibility to xenobiotic-induced breast cancer remain unclear. Since epigenetic modifications could control the expression of metabolic enzymes, our goal was to determine whether epigenome modulated metabolic networks determine susceptibility to xenobiotic-induced breast cancer. The effect of epigenetic background on predisposition to carcinogen 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer development and progression was assessed using the A(vy)/a mouse model. In a randomized block design, 22 isogenic A(vy)/a (8 yellow, 7 slightly mottled, 7 pseudoagouti) and 8 wild type non-agouti (a/a black) age matched female mice were subjected to DMBA (30 mg/kg per mouse weight) once a week for 6 weeks to induce breast cancer. Compared to pseudoagouti littermates, a significant decrease in tumour latency with increased tumour burden was observed in slightly mottled and yellow littermates (p ≤ 0.05). However, tumour latency and tumour burden were similar in non-agouti a/a mice and A(vy)/a cohorts. Network analysis of differentially expressed liver genes identified altered metabolic gene networks among agouti phenotypes. Consequently, in HPLC analyses, DMBA metabolites were significantly increased in A(vy)/a pseudoagouti mice (p ≤ 0.05). Relative to A(vy)/a slightly mottled, A(vy)/a yellow and non-agouti a/a black mice, DMBA metabolites increased nine-, eight-, and four-fold, respectively, in A(vy)/a pseudoagouti mice. In agreement with this, seven phase 2 xenobiotic detoxification genes were significantly upregulated in A(vy)/a pseudoagouti mice (p ≤ 0.05). The Results from this study suggest that epigenome modulation of xenobiotic detoxification pathways may control xenobiotic-induced breast cancer susceptibility in A(vy)/a mice.