RNA-Seq based genome-wide analysis reveals loss of inter-chromosomal regulation in breast cancer

Abstract

Abstract Breast cancer is a complex heterogeneous disease. Common hallmark features of cancer can be found. Their origin may be traced back to their intricate relationships governing regulatory programs during the development of this disease. To unveil distinctive features of the transcriptional regulation program in breast cancer, a pipeline for RNA-seq analysis in 780 breast cancer and 101 healthy breast samples, at gene expression and network level, was implemented. Inter-chromosomal relationships between genes resulted strikingly scarce in a cancer network, in comparison to its healthy counterpart. We suggest that inter-chromosomal regulation loss may be a novel feature in breast cancer. Additional evidence was obtained by independent validation in microarray and Hi-C data as well as supplementary computational analyses. Functional analysis showed upregulation in processes related to cell cycle and division; while migration, adhesion and cell-to-cell communication, were downregulated. Both the BRCA1 DNA repairing signalling and the Estrogen-mediated G1/S phase entry pathways were found upregulated. In addition, a synergistic underexpression of the γ-protocadherin complex, located at Chr5q31 is also shown. This region has previously been reported to be hypermethylated in breast cancer. These findings altogether provide further evidence for the central role of transcriptional regulatory programs in shaping malignant phenotypes.