Abstract Background: Estrogen receptor-positive (ER+) breast cancer (BC) is the most common BC subtype, which is prevalent in women and seriously threatens their health. However, the present chemotherapy for ER+ BC exists many challenges, suggesting that there is an urgent need for novel drug targets to ER+ BC. Methods: The protein quantitative trait loci (pQTLs) data of plasma proteins and genome-wide association study (GWAS) summary data of ER+ BC were searched from the Integrative Epidemiology Unit (IEU) OpenGWAS database, which were included in Mendelian randomization (MR) analysis. Five methods were employed to perform the causal inference between plasma proteins and ER+ BC, including MR-Egger, Weighted median, Simple mode, Weighted mode, and Inverse variance weighted (IVW). Moreover, the sensitivity analysis, steiger test and co-localization were carried out to further reinforce the causality between plasma proteins and ER+ BC. Finally, the phenotype scanning was implemented to search for potential diseases associated with druggable genes, and the molecular docking was also proceeded to ascertain the potential drugs for druggable genes. Results: Based on IVW, a total of 31 plasma proteins were significantly causally effected on ER+ BC, such as VEGFR-3, IL3RA, ISLR2, VEGFR-2 and MICB. The reliability of their causal relationships was validated using sensitivity analysis and steiger test. Specifically, VEGFR-3 (rs635634), IL3RA (rs115478735), ISLR2 (rs115478735), VEGFR-2 (rs635634) and MICB (rs34158769) shared the same variant with ER+ BC (rs532436) with the help of co-localization analysis (coloc.abf-PPH495%). In addition, only three symbol genes (FLT4, KDR and IL3RA) corresponding to above exposure factors existed potential drugs, such as both of FLT4 and KDR binding to Axitinib. With respect to phenotype scanning, we discovered that VEGFR-3, IL3RA and VEGFR-2 as protective factors were causally related to nausea and vomiting, BC and diabetes mellitus, respectively. Whhereas IL3RA was a risk factor for lung cancer, as well as VEGFR-2 for colorectal cancer. Conclusion: Our study supported that plasma proteins were causally connected with ER+ BC risk, especially VEGFR-3, IL3RA, ISLR2, VEGFR-2 and MICB, which might be promising drug targets for ER+ BC. Citation Format: C. Wei, L. Mengbo, Z. Hui. Discovering potential drug targets for estrogen receptor-positive breast cancer through Mendelian randomization abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-04-16.
Chen et al. (2026) studied this question.