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

TL;DR

This study shows that high levels of PSMG3 in breast cancer are linked to worse outcomes, metabolic changes, and immune system interactions, making it a potential target for treatment.

Contribution

The study identifies PSMG3 as a novel prognostic biomarker and therapeutic target in breast cancer through multi-omics analysis.

Findings

PSMG3 is significantly elevated in breast cancer and linked to poor survival outcomes.

PSMG3-high tumors show activation of hypoxia and fatty acid metabolism pathways.

PSMG3 expression correlates with specific immune cell populations in the tumor microenvironment.

Abstract

The proteasome assembly chaperone (PSMG) gene family (comprised of PSMG1, PSMG2, PSMG3, and PSMG4) plays a critical role in proteasome biogenesis; however, its involvement in breast cancer remains poorly understood. Among these chaperones, PSMG3 is uniquely and markedly elevated in breast cancer and is associated with poor clinical outcomes. We systematically investigated the roles of PSMG 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.

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