Potential Breast Anticancer Drug Targets Revealed by Differential Gene Regulatory Network Analysis and Molecular Docking: Neoadjuvant Docetaxel Drug as a Case Study

Abstract

Understanding gene-gene interaction and its causal relationship to protein-protein interaction is a viable route for understanding drug action at the genetic level, which is largely hindered by inability to robustly map gene regulatory networks. Here, we use biological prior knowledge of family-to-family gene interactions available in the KEGG database to reveal individual gene-to-gene interaction networks that underlie the gene expression profiles of 2 cell line data sets, sensitive and resistive to neoadjuvant docetaxel breast anticancer drug. Comparison of the topology of the 2 networks revealed that the resistant network is highly connected with 2 large domains of connectivity: one in which the RAF1 and MAP2K2 genes form hubs of connectivity and another in which the RAS gene is highly connected. On the contrary, the sensitive network is highly disrupted with a lower degree of connectivity. We investigated the interactions of the neoadjuvant docetaxel drug with the protein chains encoded by gene-gene interactions that underlie the disruption of the sensitive network topology using protein-protein and drug-protein docking techniques. We found that the sensitive network is likely to be disrupted by interaction of the neoadjuvant docetaxel drug with the DAXX and FGR1 proteins, which is consistent with the observed accumulation of cytoplasmic DAXX and overexpression of FGR1 precursors in cancer cell lines. This indicates that the DAXX and FGR1 proteins could be potential targets for the neoadjuvant docetaxel drug. The work, therefore, provides a new route for understanding the effect of the drug mode of action from the viewpoint of the change in the topology of gene-gene regulatory networks and provides a new avenue for bridging the gap between gene-gene interactions and protein-protein interactions which could have deep implications on mainstream drug development protocols.