Genomic evidence based on eQTL data implicates endocrine disruptors as environmental risk factors for estrogen receptor-positive breast cancer

BACKGROUND: Estrogen receptor-positive (ER+) breast cancer is the most common molecular subtype of breast cancer and is strongly influenced by hormonal and environmental factors. Endocrine-disrupting chemicals (EDCs), which interfere with hormone signaling, have been suggested to contribute to ER+ breast cancer risk, but causal mechanisms remain unclear. METHODS: We integrated chemical-gene interaction data from the TEDX and CTD databases with large-scale genomic datasets to investigate the relationship between EDC-regulated gene expression and ER+ breast cancer. A total of 5797 EDC-related genes were identified and filtered using cis-expression quantitative trait loci (cis-eQTL) data from eQTLGen. Mendelian randomization (MR) and colocalization analyses were performed using ER+ breast cancer GWAS summary statistics to assess causal associations and shared genetic signals. Interacting EDCs were mapped to colocalized genes. RESULTS: Among 4207 genes with available cis-eQTLs, 50 showed statistically significant associations (FDR < 0.05) with ER+ breast cancer. Of these, 24 genes, including CIRBP, JMJD1C, and TET2, demonstrated strong evidence of colocalization. Key EDCs, such as bisphenol A and phthalates, were identified to interact with multiple high-risk genes, suggesting potential environmental drivers of ER+ breast cancer. CONCLUSION: This study provides genetic evidence supporting the causal role of EDC-regulated gene expression in ER+ breast cancer. The integration of MR, colocalization, and chemical-gene networks offers a novel framework for identifying environmentally relevant risk factors and contributes to understanding the gene-environment mechanisms underlying hormone-dependent cancers.