MicroRNA Expression Links Transportation Environmental Burden to Late-Stage Triple-Negative Breast Cancer

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype with persistent disparities in stage at diagnosis. While transportation-related exposures are increasingly recognized as environmental health risks, the biological mechanisms linking these exposures to cancer progression remain unclear. This study evaluated whether tumor microRNAs (miRNAs), which regulate gene expression and tumor behavior, mediate the association between transportation burden and TNBC stage at diagnosis. Methods: We analyzed 434 TNBC cases from the Louisiana Tumor Registry (2009-2019). The transportation burden from the 2022 Environmental Justice Index reflects the residential proximity to high-volume roads, railways, and airports. miRNA expression was measured via high-throughput sequencing and normalized using the trimmed mean of M-values method. Three-phase analysis (screening, individual, and multiple mediation) was performed. KEGG pathway enrichment analysis assessed downstream biological pathways. Results: After adjusting for age, race, body mass index, marital status, primary payer, and concentrated disadvantage index (CDI), every 0.10 (10-percentile) increase in transportation burden rank was significantly associated with a 9% increase in the odds of late-stage TNBC diagnosis (Adjusted OR = 1.09, 95% CI: 1.01-1.17, p = 0.021). Five miRNAs significantly mediated this relationship: downregulated hsa-let-7c-5p, hsa-let-7b-5p, hsa-miR-30a-3p, and hsa-miR-92a-3p, and upregulated hsa-miR-151a-3p. Joint mediation analysis demonstrated complete mediation (indirect effect = 0.324; p = 0.027). hsa-let-7c-5p was the primary independent mediator. The enriched pathways included MAPK, PI3K-Akt, Wnt, and p53 signaling. Conclusions: These findings identified molecular pathways linking transportation-related environmental exposures to TNBC progression through dysregulation of miRNAs. By integrating environmental exposure assessment with tumor biology, this study advances our understanding of how the built environment contributes to cancer disparities.