与其他乳腺癌类型相比，三阴性乳腺癌（TNBC）在历史上治疗选择较少。因此，探索并确定可能涉及的基因可用于治疗和管理TNBC。通过这样做，我们将提供必要的数据来了解基因如何参与癌细胞的凋亡途径，以确定潜在的治疗靶点。由于TNBC的高度基因组复杂性和异质性，单个基因改变的分析可能无法揭示驱动TNBC的致病性。因此，通过搜索大量基因相互作用，可确定分子治疗基因。本研究使用整合过的生物信息学方法，如UALCAN、TNM plotter、PANTHER、GO-KEEG和PPIs，评估凋亡调节基因的基因表达、蛋白质-蛋白质相互作用（PPI）和转录因子相互作用。与正常乳腺组织相比，UALCAN中的BNIP3、TNFRSF10B、MCL1和CASP4基因表达下调。同时，BIK、AKT1、BAD、FADD、DIABLO和CASP9在bc-GeneExMiner v4.5 mRNA表达（BCGM）数据库中下调。基于GO术语富集分析，约有21个与凋亡调节基因有关的细胞过程（GO：0009987）是生物过程（BP）中的最高类别，其次是生物调节（GO：0065007）。我们确定了29个不同调节的通路，包括p53通路、血管生成、凋亡信号通路和阿尔茨海默病前体蛋白通路。我们检查了调节凋亡基因之间的蛋白质-蛋白质相互作用（PPI）；CASP3和CASP9与FADD、MCL1、TNF、TNFRSRF10A和TNFRSF10相互作用，另外，CASP3显著与CASP9、DFFA和TP53形成PPI，CASP9与DIABLO相互作用。在前10个转录因子中，雄激素受体（AR）与5个调节凋亡基因相互作用（p<0.0001；q<0.01），其次是视黄酸受体α（RARA）（p<0.0001；q<0.01）和环指蛋白（RNF2）（p<0.0001；q<0.01）。总体而言，基因表达谱、PPI和凋亡TF相互作用发现表明，27个调节凋亡基因可能用作治疗和管理TNBC的有前途的靶点。此外，在总共27个关键基因中，CASP2、CASP3、DAPK1、TNF、TRAF2和TRAF3与TNBC的总生存率显著相关（p值<0.05），它们可能在TNBC的进展中发挥重要作用，并提供有吸引力的治疗靶点，为靶向治疗提供新的候选分子。我们的研究结果表明，CASP2、CASP3、DAPK1、TNF、TRAF2和TRAF3在本研究中使用的27个特异性基因中显著与TNBC患者的总生存率差异相关，可能在TNBC的发展中发挥关键作用，提供有前途的治疗干预。版权所有©2023年，国际抗癌研究所（George J. Delinasios博士），保留所有权利。

Compared to other breast cancer types, triple-negative breast cancer (TNBC) has historically had few treatment alternatives. Therefore, exploring and pinpointing potentially implicated genes could be used for treating and managing TNBC. By doing this, we will provide essential data to comprehend how the genes are involved in the apoptotic pathways of the cancer cells to identify potential therapeutic targets. Analysis of a single genetic alteration may not reveal the pathogenicity driving TNBC due to the high genomic complexity and heterogeneity of TNBC. Therefore, searching through a large variety of gene interactions enabled the identification of molecular therapeutic genes.This study used integrated bioinformatics methods such as UALCAN, TNM plotter, PANTHER, GO-KEEG and PPIs to assess the gene expression, protein-protein interaction (PPI), and transcription factor interaction of apoptosis-regulated genes.Compared to normal breast tissue, gene expressions of BNIP3, TNFRSF10B, MCL1, and CASP4 were downregulated in UALCAN. At the same time, BIK, AKT1, BAD, FADD, DIABLO, and CASP9 was down-regulated in bc-GeneExMiner v4.5 mRNA expression (BCGM) databases. Based on GO term enrichment analysis, the cellular process (GO:0009987), which has about 21 apoptosis-regulated genes, is the top category in the biological processes (BP), followed by biological regulation (GO:0065007). We identified 29 differentially regulated pathways, including the p53 pathway, angiogenesis, apoptosis signaling pathway, and the Alzheimer's disease presenilin pathway. 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, and CASP9 with DIABLO. In the top 10 transcription factors, the androgen receptor (AR) interacts with five apoptosis-regulated genes (p<0.0001; q<0.01), followed by retinoic acid receptor alpha (RARA) (p<0.0001; q<0.01) and ring finger protein (RNF2) (p<0.0001; q<0.01). Overall, the gene expression profile, PPIs, and the apoptosis-TF interaction findings suggest 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 <0.05); they could play important roles in the progression of TNBC and provide attractive therapeutic targets that may offer new candidate molecules for targeted therapy.Our findings demonstrate that CASP2, CASP3, DAPK1, TNF, TRAF2, and TRAF3 were substantially associated with the overall survival rate (OS) difference of TNBC patients out of a total of 27 specific genes used in this study, which may play crucial roles in the development of TNBC and offer promising therapeutic interventions.Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.