Abstract：
Triple-negative breast cancer is high heterogeneous, aggressive, and metastatic with poor prognosis. Despite of advances in targeted therapies, TNBC has been reported to cause high morbidity and mortality. A rare subpopulation within the tumor microenvironment organized into a hierarchy of cancer stem cells is responsible for therapy resistance and tumor recurrence. Repurposing of antiviral drugs for cancer treatment is gaining momentum due to reduced cost, labour, and research time, but limited due to lack of prognostic, and predictive markers. The present study investigates proteomic profiling and ROC analysis to identify CD151 and ELAVL1 as potential therapy response markers for the antiviral drug 2-thio-6-azauridine (TAU) in resistant TNBC. The stemness of MDA-MB 231 and MDA-MD 468 adherent cells was enriched by culturing them under non-adherent and non-differentiation conditions. Then, CD151+ subpopulation was isolated and characterized for the enrichment of stemness. This study found that CD151 has overexpressed in stemness enriched subpopulations, and also showed CD44 high and CD24 low expression along with stem cell-related transcription factors octamer-binding transcription factor 4 (OCT4) and Sex determining Y-box 2 (SOX2). This study also found that TAU induced significant cytotoxicity and genotoxicity in the CD151+TNBC subpopulation and inhibited their proliferation by inducing DNA damage, cell cycle arrest at the G2M phase, and apoptosis. Further, a proteomic profiling study showed that the expression of CD151 along with ELAVL1, an RNA-binding protein, was significantly reduced with TAU treatment. KM plotter showed correlation of CD151 and ELAVL1 gene expression with a poor prognosis of TNBC. ROC analysis predicted and validated CD151 and ELAVL1 as best therapy response marker for TAU in TNBC. These findings provide new insight into repurposing antiviral drug TAU for treatment of metastatic and drug resistant TNBC.
摘要：
三阴性乳腺癌是高度异质性的，侵略性,转移，预后差。尽管靶向治疗取得了进展，据报道,TNBC导致高发病率和死亡率。肿瘤微环境中组织成癌症干细胞层次结构的罕见亚群负责治疗抗性和肿瘤复发。由于成本降低，用于癌症治疗的抗病毒药物的再利用正在获得势头。劳动，和研究时间，但由于缺乏预后，和预测标记。本研究调查了蛋白质组学分析和ROC分析，以鉴定CD151和ELAVL1作为耐药TNBC中抗病毒药物2-硫代-6-氮唑啶（TAU）的潜在治疗反应标志物。通过在非贴壁和非分化条件下培养MDA-MB231和MDA-MD468贴壁细胞来富集它们的干性。然后，分离了CD151亚群，并对其进行了干细胞富集的表征。这项研究发现，CD151在干性丰富的亚群中过表达，并且还显示CD44高表达和CD24低表达以及干细胞相关转录因子八聚体结合转录因子4（OCT4）和性别决定Y-box2（SOX2）。本研究还发现TAU在CD151+TNBC亚群中诱导了显著的细胞毒性和遗传毒性,并通过诱导DNA损伤来抑制其增殖,细胞周期停滞在G2M期，和凋亡。Further,蛋白质组学研究表明，CD151与ELAVL1（一种RNA结合蛋白）的表达，用TAU治疗显着降低。KM绘图仪显示CD151和ELAVL1基因表达与TNBC预后不良相关。ROC分析预测并验证了CD151和ELAVL1是TNBC中TAU的最佳治疗反应标志物。这些发现为重新利用抗病毒药物TAU治疗转移性和耐药性TNBC提供了新的见解。
