Cuproptosis scoring system identifies novel molecular subtypes and modulates biological behavior in breast cancer

Cuproptosis, a regulated mechanism of cell death mediated by copper, significantly influences tumor progression, prognosis, and antitumor immunity. Although cuproptosis-related genes (CRGs) exhibit therapeutic potential in oncology, their mechanistic role in the pathogenesis of breast cancer (BRCA) remains incompletely characterized. Gene expression analysis was conducted utilizing UCSC-XENA data alongside GSE20685 from the Gene Expression Omnibus (GEO) database. The expression and mutation profiles of BRCA samples were examined using the R software package. Drawing from existing literature on CRGs, a total of 52 CRGs were identified for analysis. Patients were categorized into four distinct CRG subtypes through unsupervised consensus clustering. The MsigDB database facilitated the comparison of pathway differences among the four subtypes, while the distribution of samples across these subtypes and the variations in immune infiltration were also assessed. Genes exhibiting Cox p-values < 0.0001 were selected for further validation. Based on the identified genes, the CRG score (principal component 1 + principal component 2) was computed, and the relationships between classification, CRG score, and prognosis were analyzed. Furthermore, the GSCA database was employed to investigate the expression, mutation, copy number variation, and methylation differences between high and low CRG score groups, alongside their correlations with drug sensitivity and clinical characteristics. In total, 25 CRGs in BRCA were enrolled to identify four distinct subtypes. The expression levels of these CRGs varied among the four subtypes, further elucidating the relationship between clinical characteristics (such as type, stage, TNM classification, metastasis, age, full state and full time) and gene expression. Functional and multi-omic analyses of immune infiltration demonstrated significant variability in immune cell infiltration across various subtypes, including B cells and myeloid-derived suppressor cells (MDSCs). Subsequently, principal component analysis (PCA) classified BRCA patients into high and low scoring groups. The analysis revealed that patients in the high-scoring group experienced significantly improved long-term clinical outcomes compared to those in the low-scoring group. Furthermore, survival status, M stage, and recurrence of metastasis indicated that deceased patients, those in M1 stage, and metastatic patients exhibited lower scores. The expression of immune checkpoints in the high CRGs score group was found to be low, alongside a low tumor mutation burden (TMB) and microsatellite instability (MSI), with few gene mutations observed. This suggests that individuals in the low CRGs group may have a greater opportunity to benefit from immunotherapy. Through our comprehensive analysis of CRGs, we have elucidated their extensive regulatory effects on immune response, clinical features, and prognosis. The cuproptosis subtype effectively differentiates various clinical and molecular characteristics of BRCA. Additionally, the cuproptosis score emerges as a promising biomarker for predicting BRCA prognosis and assessing the benefits of immunotherapy and chemotherapy.