RESUMO
Alterations to transcriptional regulation are an important factor in breast cancer. Noncoding RNA, such as microRNA (miR), have very influential roles in the transcriptional regulation of genes. Transcriptional regulation can be successfully modeled and analyzed using complex network theory. Particularly, interactions between two distinct classes of biological elements, such as miR and genes, can be approached through the bipartite network formalism. Based on bipartite network properties, it is possible to identify highly influential miRs in the network, such as those that have a large number of connections indicating regulation of a large set of genes. Some miRs in a network are nonredundant, which indicates that they are solely responsible of the regulation of a particular set of genes, which in turn may be associated to a particular biological process. We hypothesize that highly influential, nonredundant miRs, which we call Commodore miRs (Cdre-miRs), have an important role on the control of biological functions through transcriptional networks. In this work, we analyze the regulation of gene expression by miRs in healthy and cancerous breast tissue using bipartite miR-gene networks inferred from the Cancer Genome Atlas (TCGA) expression data. We observe differences in the degree, clustering coefficient and redundancy distributions for miRs and genes in the network, indicating differences in the way that these elements interact with each other. Furthermore, we identify a small set of five Cdre-miRs in the breast cancer network: miR-190b, miR-let7i, miR-292-b, miR-511, and miR-141. The neighborhood of genes controlled by each of these miRs is involved in particular biological functions such as dynein structure-associated processes, immune response, angiogenesis, cytokine activity, and cell motility. We propose that these Cdre-miRs are important control elements of biological functions deregulated in breast cancer.
RESUMO
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.