<i>UBE2C</i> as a prognostic biomarker and immune modulator in breast cancer: mechanistic insights and therapeutic potential

Abstract Objectives Despite clinical advancements, challenges persist in breast cancer (BRCA) management, particularly regarding the ubiquitin-proteasome system. This study aims to comprehensively investigate the diagnostic, prognostic, and therapeutic roles of UBE2C . Methods Multi-omics data from 1,097 TCGA-BRCA samples were analyzed using subtype-stratified survival analyses. The tumor-immune microenvironment was profiled via deconvolution algorithms. Biological mechanisms were investigated using GSEA and DepMap functional genomic screens. Pharmacogenetic profiling and molecular docking were employed to identify targeted therapeutic vulnerabilities. Results UBE2C was significantly overexpressed in tumor tissues, demonstrating exceptional discriminatory power (AUC: 0.972). High expression correlated positively with genomic instability markers, including tumor mutation burden (TMB) and microsatellite instability. Clinically, elevated UBE2C predicted worse overall and relapse-free survival, particularly in advanced-stage tumors and low-TMB patients. At the transcriptomic and functional-genomic level, UBE2C is critical for cell viability, and its overexpression is associated with cell cycle dysregulation and TSC/mTOR pathway activation; genetic knockout resulted in growth inhibition. Furthermore, UBE2C overexpression is strongly associated with an immunosuppressive microenvironment, correlating negatively with anti-tumor effector cells and positively with regulatory T cells and checkpoints like PD-1, PD-L1, and CTLA4. Pharmacogenetic analysis indicated that UBE2C overexpression is associated with increased sensitivity to the JAK1/2 inhibitor Ruxolitinib. Molecular docking simulations revealed a structural basis for this vulnerability, showing that Ruxolitinib occupies a binding pocket within the UBE2C protein structure, stabilized by a critical hydrogen bond with residue ILE113. This structural stability suggests a potential therapeutic vulnerability associated with UBE2C overexpression and JAK1/2 inhibition. Conclusions UBE2C is a robust diagnostic and prognostic biomarker. Its observational association with aggressive tumour biology, immune evasion gene signatures, and candidate therapeutic vulnerability to Ruxolitinib suggests a hypothesis-generating framework for future experimental and clinical investigation.