Abstract
BACKGROUND: Peroxisomes are increasingly linked to cancer development, yet the prognostic role of peroxisome-related genes (PRGs) in breast cancer remains unclear. OBJECTIVE: This study aimed to construct a prognostic model based on PRG expression in breast cancer to clarify their prognostic value and clinical implications. METHODS: Transcriptomic data from TCGA and GEO were used for training and validation cohorts. TME characteristics were analyzed with ESTIMATE, MCP-counter, and CIBERSORT algorithms. qPCR validated mRNA expression levels of risk genes, and data analysis was conducted in R. RESULTS: Univariate and multivariate Cox regression identified a 7-gene PRG risk signature (ACBD5, ACSL5, DAO, NOS2, PEX3, PEX10, and SLC27A2) predicting breast cancer prognosis in training (n=1069), internal validation (n=327), and external validation (merged from four GEO datasets, n=640) datasets. While basal and Her2 subtypes had higher risk scores than luminal subtypes, a significant prognostic impact of the PRG risk signature was seen only in luminal subtypes. The high-risk subgroup exhibited a higher frequency of focal synonymous copy number alterations (SCNAs), arm-level amplifications and deletions, and single nucleotide variations. These increased genomic aberrations were associated with greater immune suppression and reduced CD8+ T cell infiltration. Bulk RNA sequencing and single-cell analyses revealed distinct expression patterns of peroxisome-related genes (PRGs) in the breast cancer TME: PEX3 was primarily expressed in malignant and stromal cells, while ACSL5 showed high expression in T cells. Additionally, the PRG risk signature demonstrated efficacy comparable to that of well-known biomarkers for predicting immunotherapy responses. Drug sensitivity analysis revealed that the PRG high-risk subgroup was sensitive to inhibitors of BCL-2 family proteins (BCL-2, BCL-XL, and MCL1) and other kinases (PLK1, PLK1, BTK, CHDK1, and EGFR). CONCLUSION: The PRG risk signature serves as a promising biomarker for evaluating peroxisomal activity, prognosis, and responsiveness to immunotherapy in breast cancer.