Exploring the role of post-translational modulators of transcription factors in triple-negative breast cancer gene expression

Abstract

Triple negative breast cancer (TNBC) is a sub type of breast cancers, and is responsible for numerous deaths worldwide. Due to lack of any of the three hormone receptors (ER, PR and HER2) commonly existing in other breast cancers, current targeted drug therapies are unavailable for this disease. Therefore, by exploring molecular regulatory network of TNBC, which includes transcription factors (TFs), modulators and target genes, it can be possible to determine treatment measures for this disease. In this study, we conducted a systematic investigation in these three key drivers to explain the regulation of TFs and modulators on target gene expression in several biological processes related to carcinogenesis. By integrating TFs with their modulators, we constructed regulatory networks. Following a hierarchical regulatory network, we identified 115 consistent motifs consisting of 52 TFs, 103 modulators (in which 11 are oncogenes, OCGs and nine are tumor suppressor genes, TSGs) and 81 target genes. All these 115 unique genes from the consistent motif of TNBC-related gene regulation were enriched with most of the functional categories related to BC or TNBC progression. The network analysis showed that the regulatory signals from the TSG and/or OCG modulators were transduced to the TFs and then to the target genes. Functional enrichment analysis indicated that most of the TSGs and OCGs were interacted and co-regulated in numerous cellular processes, including DNA damage, immune system development, gene expression, epidermal growth factor receptor signalling pathway, and response to estrogen. In mutational analysis of TFs, the maximum frequency (10%) of gene alteration was observed in TRPS1, which also showed over expression across TNBC tumor samples. These results may help to understand the activity of the novel regulator TRPS1 on TNBC patient risk profile and their post-translational activity.