Gene expression and epigenetic profiles of mammary gland tissue: Insight into the differential predisposition of four rat strains to mammary gland cancer

• Rats are excellent models for studying breast cancer.
• Different rat strains differ in cancer susceptibility.
• We compared epigenetic profiles of mammary glands of rats of four strains.
• We have identified important differences in epigenetic profiles of rat strains.
• These epigenetic profiles may underlie cancer susceptibility.

Rats are excellent experimental models for studying breast cancer, but rat strains differ in susceptibility. Among the four strains used in this study, Fischer rats are less susceptible to spontaneous breast cancer, yet they are highly prone to extremely severe metastatic and drug-resistant tumors, in those case where they actually develop the disease. In contrast, Sprague Dawley rats are the most susceptible to spontaneous breast cancer among the strains. ACI rats are highly prone to estrogen-induced cancer. Long–Evans rats are commonly used in mammary gland carcinogenesis studies. The molecular mechanisms of differential breast cancer susceptibility among rat strains are not well understood. Here, gene expression analysis was conducted in the mammary gland tissue of four rat strains – August × Copenhagen Irish (ACI), Long Evans, Fischer-344 and Sprague Dawley – to evaluate possible explanations for the differing breast cancer predispositions. According to the DAVID functional annotation analysis, there were at least eleven, five, and one significantly different pathways, respectively, in Fischer-344, Long–Evans and Sprague Dawley rats, in comparison to ACI rats. Two strains, Fischer-344 and Long–Evans, displayed differential expression in the complement and coagulation cascades, chemokine signaling, PPAR signaling, renin–angiotensin system, ECM-receptor interaction, focal adhesion and glutathione metabolism pathways. The only pathway that was significantly different between the Sprague Dawley and the ACI rats was the ribosome pathway. Our data indicate that general cancer susceptibility and predisposition to the development of aggressive and metastatic cancer are independent genetic conditions. Moreover, we have identified several important differences in the basal epigenetic profile of four rat strains with varying degrees of susceptibility to spontaneous and induced mammary carcinogenesis.

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