IL3RA identified as novel biomarker and therapeutic target for ER+ breast cancer through plasma proteome-wide mendelian randomization and TCGA database analysis

Estrogen receptor-positive (ER+) breast cancer, a leading cause of female cancer mortality, faces therapeutic challenges due to endocrine resistance. Plasma proteins, bridging genetic variation and disease phenotypes, offer potential biomarkers and therapeutic targets, yet their causal roles in the pathogenesis of ER+ breast cancer remain underexplored. Using two-sample Mendelian randomization (TSMR) and Bayesian colocalization, we analyzed associations between plasma protein quantitative trait loci from deCODE/Fenland cohorts and ER+ breast cancer. DSigDB predicted drugs targeting identified protein, while TCGA assessed the prognostic value. TSMR identified 38 causal plasma proteins (deCODE), with Bayesian analysis prioritizing 12 candidates. IL3RA emerged as stable and novel protective factor, validated in Fenland data. TCGA revealed reduced IL3RA expression in ER+ tumors, with higher levels correlating with improved survival and favorable clinicopathological features, particularly in ER+/PR+ cases. Tumor microenvironment analysis revealed that IL3RA expression levels significantly correlated with immune landscape alterations in ER+ breast cancer. Immune infiltration analysis demonstrated significant associations between IL3RA expression levels and multiple immune cell populations in ER+ breast cancer, particularly CD8+ T cells, neutrophils, M0 macrophages, and M2 macrophages. DSigDB identified panobinostat, arbutin, clindamycin, cimetidine, and chlorzoxazone as IL3RA-targeting drugs. Our study identified IL3RA as novel biomarker and therapeutic target for ER+ breast cancer. Further validation and mechanistic studies are warranted to advance precision oncology strategies for ER+ breast cancer management.