Prognostic and Therapeutic Implications of Genes Associated with Apoptosis and Protein-Protein Interactions in Triple-Negative Breast Cancer

Abstract

<b>Abstract ID 54503</b> <b>Poster Board 446</b> Triple-negative breast cancer (TNBC) has historically had fewer treatment alternatives than other breast cancer types. Therefore, it is critical to explore and pinpoint potential biomarkers that could be utilized in treating TNBC. By doing this, we will significantly enhance a patient’s prognosis and quality of life. Apoptosis-controlling genes could be manipulated to increase the death of cancer cells. It is essential to comprehend how the genes involved in the apoptotic pathway interact to identify potential therapeutic targets. Therefore, the current study is aimed to evaluate the gene expression, protein-protein interaction (PPI), and transcription factor interaction of 27 apoptosis-regulated genes in TNBC using integrated bioinformatics methods to assess the gene expression, protein-protein interaction (PPI) and transcription factor interaction. Our findings demonstrated that <i>CASP2, CASP3, DAPK1, TNF, TRAF2,</i> and <i>TRAF3</i> were substantially associated with the overall survival rate (OS) difference of TNBC patients. The results also show that breast tissue gene expressions of BNIP3, TNFRSF10B, MCL1, and CASP4 were downregulated compared to normal breast tissue in UALCAN. At the same time, <i>BIK, AKT1, BAD, FADD, DIABLO,</i> and <i>CASP9</i> were downregulated in bc- GeneExMiner v4.5 mRNA expression (BCGM) databases. Based on the GO term enrichment analysis, the Cellular process (GO:0009987), which has about 21 apoptosis-regulated genes, is the top category in the biological process (BP), followed by biological regulation (GO:0065007). We identified 29 pathways, including p53, angiogenesis, and apoptosis signaling. We examined the PPIs between the genes that regulate apoptosis; CASP3 and CASP9 interact with FADD, MCL1, TNF, TNFRSRF10A, and TNFRSF10; additionally, CASP3 significantly forms PPIs with CASP9, DFFA, and TP53, while CASP9 with DIABLO. In the top 10 transcription factors, the androgen receptor (AR) interacts with five apoptosis-regulated genes (p&lt;0.0001; q&lt;0.01), followed by RARA (Retinoic Acid Receptor Alpha) (p&lt;0.0001; q&lt;0.01) and RNF2 (Ring Finger Protein) (p&lt;0.0001; q&lt;0.01). Overall, the gene expression profile, the PPIs, and the apoptosis-TF interaction findings suggested that the 27 apoptosis-regulated genes might be used as promising targets in treating and managing TNBC. Furthermore, from a total of 27 key genes, CASP2, CASP3, DAPK1, TNF, TRAF2, and TRAF3 were significantly correlated with poor overall survival in TNBC (p-value &lt; 0.05), which could play essential roles in the progression of TNBC and provide attractive therapeutic targets that may offer new candidate molecules for targeted therapy. It was concluded from this study that genetic alterations altering apoptosis could be possible biomarkers for the prognosis and facilitate the search for alternative treatment targets for TNBC. This research was supported by grants from the National Institute of Minority Health and Health Disparities of the National Institutes of Health through Grant Number U54 MD 007582