Ferroptosis-related differential gene expression and immune correlates in luminal a subtype breast cancer: a prognostic model approach

Abstract

This study aimed to identify reliable prognostic biomarkers and novel therapeutic targets for Luminal A subtype breast cancer, a prevalent subtype with unmet needs in overcoming endocrine resistance. Given the rising global incidence of breast cancer, high recurrence/drug resistance rates in Luminal A patients, and limited research on ferroptosis in this subtype, we analyzed 421 Luminal A subtype breast cancer samples and 113 adjacent normal tissues from The Cancer Genome Atlas (TCGA) database. Differential expression analysis (log₂|fold change|>1, p < 0.05) and univariate Cox regression for overall survival (OS) identified 12 ferroptosis-related differentially expressed genes (DEGs) with prognostic value. Using Lasso-Cox regression (10-fold cross-validation to avoid overfitting), we further optimized these into a 9-gene prognostic model. Univariate and multivariate Cox regression confirmed the model-derived risk score as an independent prognostic factor for OS (HR = 3.896, 95% CI = 2.195–6.916, p < 0.001) in TCGA. External validation in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (584 Luminal A samples) demonstrated consistent prognostic performance (log-rank p < 0.001), confirming the model’s robustness. Functional enrichment analysis showed these genes were enriched in ferroptosis-related pathways, including “lipid biosynthetic process”(Gene Ontology) and “FoxO signaling pathway” (Kyoto Encyclopedia of Genes and Genomes). Single-sample gene set enrichment analysis revealed high-risk groups had increased infiltration of immunosuppressive cells (mast cells, neutrophils, regulatory T cells) and elevated type II interferon response, while low-risk groups had higher type I interferon response. Spearman’s correlation analysis identified ENPP2 as a key mediator of immune escape, with a strong positive correlation with PD-1 (r = 0.46, p = 8.7e-24). This 9-gene ferroptosis-related model provides a robust tool for OS prediction in Luminal A subtype breast cancer and highlights ENPP2 as a potential target for combining ferroptosis inducers with immune checkpoint inhibitors—offering a novel strategy for endocrine-resistant patients.