Proteasome Assembly Chaperone 3 Defines Metabolic-Immune Programs and Poor Prognosis in Breast Cancer via Multi-Omics Approaches

The proteasome assembly chaperone (<i>PSMG</i>) gene family (comprised of <i>PSMG1</i>, <i>PSMG2</i>, <i>PSMG3</i>, and <i>PSMG4</i>) plays a critical role in proteasome biogenesis; however, its involvement in breast cancer remains poorly understood. Among these chaperones, <i>PSMG3</i> is uniquely and markedly elevated in breast cancer and is associated with poor clinical outcomes. We systematically investigated the roles of <i>PSMG</i> family genes in breast cancer by integrating multi-cohort genomic and transcriptomic datasets, including TCGA-BRCA, METABRIC, and multiple NCBI GEO cohorts. Comprehensive bioinformatics analyses were performed using bulk RNA sequencing and single-cell RNA sequencing data. A gene set enrichment analysis (GSEA) and immune infiltration analyses (CIBERSORT and TIMER) were applied to characterize dysregulated biological pathways, tumor microenvironmental features, and clinical relevance. In addition, molecular docking analyses were conducted to assess the druggability and binding potential of PSMG family proteins with selected small-molecule inhibitors. Elevated PSMG3 expression was consistently associated with poor survival outcomes across multiple breast cancer cohorts. Functional enrichment analyses revealed that PSMG3-high tumors were characterized by activation of hypoxia-related signaling pathways and dysregulated fatty acid metabolism, suggesting a role for PSMG3 in metabolic reprogramming. Immune deconvolution analyses further demonstrated significant correlations between PSMG3 expression and distinct immune cell populations within the tumor microenvironment. These findings were supported by single-cell transcriptomic profiling, which revealed subtype-specific expression patterns of PSMG3 in malignant epithelial cell populations. This integrative multi-omics analysis identified PSMG3 as a clinically relevant proteasome assembly chaperone associated with aggressive breast cancer phenotypes, metabolic dysregulation, and tumor immune contexture. Collectively, these results highlight PSMG3 as a promising prognostic biomarker and potential therapeutic target in breast cancer.