Epigenetic programs shaping lung metastasis in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a major cause of cancer mortality, with distant metastases presenting a significant clinical challenge. While epigenetic mechanisms like DNA methylation are known to influence TNBC progression, their specific role in driving metastasis remains underexplored. To address this gap, we performed comprehensive multi-omics analysis, integrating epigenomic and transcriptomic profiles from TNBC xenograft models and patient cohorts. Genome-wide DNA methylation profiling of primary tumors, lymph nodes, and lung metastases from xenografts revealed pronounced global hypomethylation in lung lesions, consistent with findings from the clinical cohort. Promoter-methylation changes were enriched in pathways linked to invasion and proliferation, and transcriptomic integration identified 22 epigenetically regulated genes. Among these, elevated AK1, SLC2A5, TPI1, and ZBTB17 expression correlated with a higher risk of lung dissemination. These findings highlight altered DNA methylation as a driver of TNBC lung colonization and identify candidate prognostic markers, emphasizing the importance of epigenetic reprogramming in organ-specific lung metastases.