SELE is associated with reduced breast cancer susceptibility: Evidence from Mendelian randomization and single-cell transcriptome

• Identified four plasma proteins (ALPI, CDH1, SELE, CNTNAP2) causally linked to breast cancer risk. • ALPI and SELE share genetic causal variants with breast cancer susceptibility via colocalization. • Molecular docking reveals high-affinity binding between the protective protein SELE and simvastatin. • SELE is significantly downregulated in breast cancer tissues across bulk and single-cell transcriptomes. The role of circulating proteins in breast cancer (BC) early diagnosis remains unclear. We investigated genetically predicted associations between circulating proteins and BC risk using Mendelian randomization (MR). This study aims to identify novel protein biomarkers through an integrative multi-omics approach. Using a two-sample MR framework, we assessed genetically determined circulating protein associations with BC risk/subtypes. Analysis incorporated large-scale protein quantitative trait loci (pQTL) and genome-wide association studies (GWAS) data, strengthened by cross-validation, sensitivity analyses (MR-Egger, MR-PRESSO), and meta-analysis. We further performed genetic colocalization, molecular docking, and phenome-wide MR (PheWAS-MR). Bulk and single-cell RNA sequencing data were analyzed to compare gene expression of causal proteins between healthy and BC tissues. This multi-layered validation enhances the robustness of causal inference. Three circulating proteins are associated with reduced BC risk—SELE (OR = 0.98, 95 % CI: 0.97–0.98), CDH1 (OR = 0.94, 95 % CI: 0.93–0.95), ALPI (OR = 0.95, 95 % CI: 0.94–0.96). CNTNAP2 is associated with elevated BC risk (OR = 1.02, 95 % CI: 1.01–1.03). Colocalization supported shared causal variants for SELE and ALPI. Molecular docking simulation indicates high binding affinity of SELE-simvastatin. SELE expression was significantly reduced in endothelial cells of BC tissue, and PheWAS-MR revealed SELE's association with 123 phenotypes, highlighting its extensive pleiotropic effects. This study provides robust genetic evidence for the causal roles of SELE, CDH1, and ALPI in reducing BC risk. The integrative proteomic-genetic-transcriptomic approach identifies potential therapeutic targets and offers new insights into BC pathogenesis, presenting hypotheses for clinical validation.