"Abstract

Breast cancer (BC) is the most common cancer in women, with metastasis as the leading cause of mortality. Persistent organic pollutants (POPs) may increase BC aggressiveness, but mechanisms remain unclear. This study examined the link between POP exposure and BC progression. We analyzed tumor samples from 89 BC patients in the METAPOP cohort, measuring 42 POPs, including dioxins, polychlorinated biphenyls (PCBs), and polybromodiphenylethers (PBDEs). Transcriptomic analysis identified genes differentially expressed in relation to POP exposure and BC aggressiveness (tumor size, metastatic risk, lymph node involvement, and estrogen receptor status). RNA sequencing of 89 tumors identified 4931 genes differentially expressed with ER status, 283 with tumor size, and 99 with metastasis. Key enriched pathways included immune response, extracellular matrix remodeling, and cell cycle regulation. Gene set enrichment analysis revealed significant overlap in pathways regulating the cell cycle, immune response, and BC hallmarks. Findings suggest that POP exposure alters tumor biology, promoting an aggressive phenotype. This study provides novel insights into the role of environmental pollutants in BC progression, emphasizing the need for further research on how POPs contribute to tumor aggressiveness."