Abstract
BACKGROUND: Per- and polyfluoroalkyl substances (PFAS), pervasive environmental contaminants, are increasingly linked to breast cancer, yet their molecular mechanisms remain unclear. This study integrates network toxicology and bioinformatics to elucidate PFAS-associated pathways and prognostic biomarkers in breast cancer. METHODS: Using the TCGA-BRCA dataset, we identified differentially expressed genes (DEGs) between normal and breast cancer tissues. We cross-referenced these genes with PFAS-related genes from the Comparative Toxicogenomics Database (CTD) to identify common targets. Enrichment analysis, network construction, and survival analysis were performed to elucidate the biological mechanisms and prognostic value. The CIBERSORT algorithm assessed immune cell infiltration, and molecular docking evaluated interactions between PFAS compounds and key genes. RESULTS: We identified 141 common DEGs, significantly enriched in pathways related to cytokine activity, growth factor activity, and chemokine receptor binding. A PFAS-toxicity target-breast cancer network illustrated potential mechanistic pathways. Six key prognostic genes (MRPL13, LEF1, ATP7B, IFNG, SFRP1, DNMT3B) were identified, forming a risk model that stratified patients with significant differences in survival. Higher risk scores were associated with advanced stages, specific histological types, and hormone receptor statuses. Immune cell infiltration analysis revealed distinct profiles between high and low-risk groups, with high-risk patients exhibiting elevated activated T cells and macrophages. Molecular docking showed strong interactions between PFAS compounds (PFOS and PFDE) and DNMT3B, suggesting potential gene function disruptions. CONCLUSION: PFAS exposure is linked to altered gene expression, immune cell infiltration, and potential disruptions in key genes, contributing to breast cancer development and progression. These findings provide insights into potential therapeutic targets and underline the importance of addressing environmental factors in breast cancer management.