Exploring microRNA interaction networks to explain the relationship between caloric restriction and breast cancer in mice

Caloric restriction (CR) —limiting average calorie intake without regressing in physical and mental activities— is known to enhance longevity and overall health and reduce aging-related disorders. The epigenetic fluctuation caused by CR in conjunction with microRNA (miRNA) expression has only been studied in the context of basic differentially expressed miRNAs and has not been used to characterize miRNA regulatory networks in a tissue- and diet-specific way. It is known that miRNAs act synergistically. However, little is known about the remodeling of miRNA interactions under different dietary restrictions and different tissues. Here we provide a novel approach to analyze miRNA-miRNA interactions and reveal different effects of dietary restriction in both blood and mammary fat pad (MFP). We analyzed miRNA expression from female C57BL/6 mice fed with three different diets: ad libitum (AL), chronic caloric restriction (CCR) with 15% CR, and intermittent caloric restriction (ICR) with three weeks of AL followed by one week 60% CR in a cyclic manner. We infer co-expression networks for each dietary group using a joint graphical model, then map the targets of the connected components of co-expression networks. To evaluate the influence on the pathways we used a network-based centrality approach to prioritize miRNAs and KEGG pathways. The miRNA miR-1a-3p is common to all conditions with high centrality, while miR-129-5p is specific to the MFP, and miR-505-5p is specific to only blood in the CCR group. In our analysis using the ranking according to the eigenvector centrality in the co-expression networks for the influence on pathways, we revealed that the KEGG pathways such as "Breast cancer" and "mTOR signaling pathway" increased their importance by CCR diet in blood. In addition to that, we revealed the KEGG pathways "p53 signaling pathway" and "Fatty acid degradation" increased their importance by CCR in MFP. These pathways are well-known regulators of both aging and cancer. mTOR and MAPK signaling pathway has crosstalk with many other cancer-related pathways, and these pathways may be the key to the anti-cancer mechanism of the CCR diet.