Mutational Landscape Analysis of BRCA1/2 and Identification of Extracellular-Vesicle-Related Biomarkers in Triple-Negative Breast Cancer.

Background: Triple-negative breast cancer (TNBC), defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression, is associated with increased BRCA1/2 mutation rates. Extracellular vesicles (EVs) play a pivotal role in TNBC progression. This study aimed to analyze BRCA1/2 mutations and identify EV-related biomarkers for TNBC by employing TNBC-related datasets and EV-related genes (EVRGs). Methods: Initially, BRCA1/2 mutations in TNBC patients were examined. Differentially expressed EVRGs (DE-EVRGs) were identified by integrating the results of both differential expression analysis and weighted gene co-expression network analysis (WGCNA). Biomarkers were identified using Receiver Operating Characteristic (ROC) and Kaplan-Meier (K-M) analyses. Finally, functional enrichment, drug prediction, molecular docking, and reverse transcription quantitative polymerase chain reaction (RT-qPCR) analyses were performed. Results: Waterfall plots indicated that TP53 exhibited the highest mutation frequency in both the mutation (MUT) and wild-type (WT) group. Four distinct types of immune cells (for example, eosinophils and neutrophils) showed significantly elevated expression levels in the WT group. Notably, PLA2G5 was identified as a biomarker of TNBC and its expression was significantly lower in TNBC (p = 0.0025). Functional analysis demonstrated that PLA2G5 is enriched in the "drug metabolism cytochrome P450" pathway. Finally, 20 drugs targeting PLA2G5 were identified, among which leukotriene C4 demonstrated a binding affinity of -7.2 kcal/mol. This finding suggests that leukotriene C4 has potential therapeutic applications for the treatment of TNBC. Conclusions: Our study found significant differences between the MUT and WT groups, identifying PLA2G5 as a biomarker for TNBC and offering a theoretical basis for TNBC treatment.