Common Biomarkers and Pathogenesis of Inflammatory Bowel Disease and Breast Cancer: Mendelian Randomization and Multi-Omics Studies

Daqing Zhang,1 Yongjun Guan,1 Haitao Tang,2 Qingze Xue,2 Xiaoqiang Li,2 Xu Bin,3 Faping You2 1Department of General Surgery, Beijing Friendship Hospital, Capital Medical University,State Key Lab of Digestive Health,National Clinical Research Center for Digestive Diseases, Beijing, People’s Republic of China; 2Department of Breast Surgery, Shengli Oilfield Central Hospital, Dongying, Shandong, People’s Republic of China; 3Department of Pathology, Shengli Oilfield Central Hospital, Dongying, Shandong, People’s Republic of ChinaCorrespondence: Faping You, Email [email protected] Xu Bin, Email [email protected]: Inflammatory bowel disease (IBD) and breast cancer represent significant global health burdens. Although epidemiological studies have suggested a potential link between them, the causal relationship and underlying molecular mechanisms remain unclear. This study employed Mendelian randomization (MR) and multi-omics approaches to investigate the causal association between IBD and breast cancer and to explore shared genetic biomarkers and pathological pathways.Methods: A two-sample MR analysis was performed using genome-wide association study (GWAS) data. Shared genes were identified and validated using the GEO and TCGA databases. THBS3 expression was further verified in human breast cancer tissues via immunohistochemistry and RT-PCR. Immune infiltration analysis, drug sensitivity assessment, molecular docking, ceRNA network construction, and pathway enrichment analyses (GSEA and GSVA) were conducted to explore the functional role of THBS3.Results: MR analysis indicated that IBD significantly increases the risk of breast cancer. THBS3 was identified as a commonly overexpressed gene in both diseases and was associated with poor prognosis. THBS3-high breast cancer patients exhibited resistance to Dinaciclib, Daporinad, and Rapamycin. Molecular docking and dynamics simulations confirmed a strong binding affinity between THBS3 and Rapamycin. A ceRNA network linked THBS3 to miR-423-5p and chemotherapy resistance-related lncRNAs. Pathway analyses revealed THBS3 involvement in extracellular matrix receptor interaction and proteasome pathways.Conclusion: This study provides genetic evidence supporting IBD as a risk factor for breast cancer and highlights THBS3 as a key shared biomarker. THBS3 may promote breast cancer progression through immune regulation, ECM remodeling, and drug resistance mechanisms, suggesting its potential as a therapeutic target. These findings support enhanced breast cancer screening in IBD patients.Keywords: IBD, Crohn’s disease, ulcerative colitis, breast cancer, Mendelian randomization