Unraveling the Complexities in TNBC Gene Interaction Networks Towards Better Therapeutics
Priyanga Paranthaman, HemaNandini Rajendran Krishnamoorthy, Selvakumar Veluchamy, K. Ramanathan, Shanthi Veerappapillai · Biotechnology and Applied Biochemistry · 2025
Triple-negative breast cancer (TNBC) presents a substantial global health challenge due to its highly aggressive and invasive traits. To address this, the present study employed network-based analysis using protein-protein interaction (PPI) data to identify hub proteins and their functional insights. We constructed a PPI network consisting of 1413 dysregulated genes in TNBC. These hub genes displayed 5763 interactions. The downstream analysis identified TP53, SRC, EP300, AKT1, HSP90AA1, MAPK3, EGFR, and SMAD3 as hub proteins based on topological parameters and functional enrichment analyses. The DGIdb data were exploited to investigate the link between drugs and the identified hub genes. Collectively, the findings showed that no Food and Drug Administration (FDA)-approved drugs exist to target the EP300 protein. This situation necessitates the discovery of potential repurposed candidate against EP300 protein from the repository of 2147 FDA-approved compounds. Precisely, molecular docking, MM-GBSA, and ML-based rescoring analysis identified DB06137 (tirbanibulin) as a lead compound. Moreover, the dynamic behavior of DB06137 reinforces its exceptional structural stability with EP300, indicating its potential for novel therapeutic applications. We hypothesize that tirbanibulin interacts either with the regulatory regions of EP300 through allosteric inhibition or indirectly by altering upstream signaling pathways. Given the vital role of drug repurposing, experimental investigations on tirbanibulin unanticipated effects against EP300 are an interesting future direction.