Identification of cuproptosis-related patterns and construction of a scoring system for predicting prognosis, tumor microenvironment-infiltration characteristics, and immunotherapy efficacy in breast cancer

Abstract

BackgroundCuproptosis, a recently discovered refreshing form of cell death, is distinct from other known mechanisms. As copper participates in cell death, the induction of cancer cell death with copper ionophores may emerge as a new avenue for cancer treatment. However, the role of cuproptosis in tumor microenvironment (TME) cell infiltration remains unknown.MethodsWe systematically evaluated the cuproptosis patterns in The Cancer Genome Atlas (TCGA) database in breast cancer (BRCA) samples based on 10 cuproptosis-related genes (CRGs), and correlated these patterns with the prognosis and characteristics of TME cell infiltration. A principal component analysis algorithm was used to construct a cuproptosis score to quantify the cuproptosis pattern in individual tumors. Further, the relationships between the cuproptosis score and transcription background, clinical features, characteristics of TME cell infiltration, drug response, and efficacy of immunotherapy were assessed.ResultsTwo distinct cuproptosis patterns with distinct prognoses were identified; their TME characteristics were found to be consistent with the immune-excluded and immune-inflamed phenotypes, respectively. The cuproptosis patterns in individual patients were evaluated using the cuproptosis score based on the cuproptosis phenotype-related genes, contributing to distinguishing biological processes, clinical outcome, immune cell infiltration, genetic variation, and drug response. Univariate and multivariate Cox regression analyses verified this score as an independent prognostic predictor in BRCA. A high cuproptosis score, characterized by immune activation, suggests an inflamed tumor and immune-inflamed phenotype with poor survival and a low cuproptosis score, characterized by immune suppression, indicates a non-inflamed tumor and immune-excluded phenotype with better survival. Significant differences were observed in the IC50 between the high and low cuproptosis score groups receiving chemotherapy and targeted therapy drugs. In the two immunotherapy cohorts, patients with a higher cuproptosis score experienced considerable therapeutic advantages and clinical benefits.ConclusionsThis study is the first to elucidate the prominent role of cuproptosis in the clinical outcome and the formation of TME diversity and complexity in BRCA. Estimating cuproptosis patterns in tumors could help predict the prognosis and characteristics of TME cell infiltration and guide more effective chemotherapeutic and immunotherapeutic strategies.

Prognostic Significance of Cuproptosis-Related Gene Signatures in Breast Cancer Based on Transcriptomic Data Analysis

“…The area under the ROC curve in both the training and validation sets at 1, 3 and 5 years was (AUC) 0.686, 0.722 and 0.727, and 0.626, 0.663 and 0.678, respectively ( Figure 4 F and Figure 5 C). In addition, we compared our risk model with other established models and found that the AUC of our risk model was higher than that of others ( Figure S3A–F ) [ 17 , 18 ].…”

Cuproptosis-associated ncRNAs predict breast cancer subtypes

“…Deng et al harnessed machine learning techniques to identify copper death-related genes, ultimately constructing a novel ceRNA network and risk model tailored to breast cancer [ 75 ]. Li et al devised a copper death scoring system aimed at forecasting tumor microenvironment infiltration characteristics and gauging the efficacy of immunotherapy [ 76 ]. These investigations have primarily concentrated on leveraging copper death mechanisms to forecast the prognosis of breast cancer patients.…”

The therapeutic and prognostic role of cuproptosis-related genes in triple negative breast cancer

“…Copper accumulates in the cells and directly binds to lipoylated components of the tricarboxylic acid cycle. This leads to abnormal aggregation of the lipoylated protein and the subsequent loss of the iron-sulfur cluster protein, which together result in proteotoxic stress and ultimately cell death [ 7 ].…”

“…So far, cuproptosis-related modification patterns have been reported to depict the tumor microenvironment/immunotherapy/prognosis in kidney renal clear cell carcinoma [ 10 ], clear cell renal cell carcinoma [ 11 ], hepatocellular carcinoma [ 12 ], and colorectal cancer [ 13 ]. Among the limited bioinformatics studies in BC, it is true that estimating cuproptosis patterns in tumors could help predict the prognosis and characteristics of TME cell infiltration and guide more effective chemotherapeutic and immunotherapeutic strategies [ 7 ]. However, current BC studies based on publicly available data only use the overall BC cases, and in particular, there are very limited research of cuproptosis involvement in the prognosis of TNBC by bioinformatic analysis [ 14 , 15 ].…”