An Information Theoretical Multilayer Network Approach to Breast Cancer Transcriptional Regulation

Breast cancer is a complex, highly heterogeneous disease at multiple levels ranging from its genetic origins and molecular processes to clinical manifestations. This heterogeneity has given rise to the so-called intrinsic or molecular breast cancer subtypes. Aside from classification, these subtypes have set a basis for differential prognosis and treatment. Multiple regulatory mechanisms-involving a variety of biomolecular entities-suffer from alterations leading to the diseased phenotypes. Information theoretical approaches have been found to be useful in the description of these complex regulatory programs. In this work, we identified the interactions occurring between three main mechanisms of regulation of the gene expression program: transcription factor regulation, regulation via noncoding RNA, and epigenetic regulation through DNA methylation. Using data from The Cancer Genome Atlas, we inferred probabilistic multilayer networks, identifying key regulatory circuits able to (partially) explain the alterations that lead from a healthy phenotype to different manifestations of breast cancer, as captured by its molecular subtype classification. We also found some general trends in the topology of the multi-omic regulatory networks: Tumor subtype networks present longer shortest paths than their normal tissue counterpart; epigenomic regulation has frequently focused on genes enriched for certain biological processes; CpG methylation and miRNA interactions are often part of a regulatory core of conserved interactions. The use of probabilistic measures to infer information regarding theoretical-derived multilayer networks based on multi-omic high-throughput data is hence presented as a useful methodological approach to capture some of the molecular heterogeneity behind regulatory phenomena in breast cancer, and potentially other diseases.