Network analysis of EMT and MET micro-RNA regulation in breast cancer

Over the last years, microRNAs (miRs) have shown to be crucial for breast tumour establishment and progression. To understand the influence that miRs have over transcriptional regulation in breast cancer, we constructed mutual information networks from 86 TCGA matched breast invasive carcinoma and control tissue RNA-Seq and miRNA-Seq sequencing data. We show that miRs are determinant for tumour and control data network structure. In tumour data network, miR-200, miR-199 and neighbour miRs seem to cooperate on the regulation of the acquisition of epithelial and mesenchymal traits by the biological processes: Epithelial-Mesenchymal Transition (EMT) and Mesenchymal to Epithelial Transition (MET). Despite structural differences between tumour and control networks, we found a conserved set of associations between miR-200 family members and genes such as VIM, ZEB-1/2 and TWIST-1/2. Further, a large number of miRs observed in tumour network mapped to a specific chromosomal location in DLK1-DIO3 (Chr14q32); some of those miRs have also been associated with EMT and MET regulation. Pathways related to EMT and TGF-beta reinforce the relevance of miR-200, miR-199 and DLK1-DIO3 cluster in breast cancer. With this approach, we stress that miR inclusion in gene regulatory network construction improves our understanding of the regulatory mechanisms underlying breast cancer biology.