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The role of ferroptosis in breast cancer patients: a comprehensive analysis.

ABSTRACT: Breast cancer (BC) affects the breast tissue and is the second most common cause of mortalities among women. Ferroptosis is an iron-dependent cell death mode that is characterized by intracellular accumulation of reactive oxygen species (ROS). We constructed a prognostic multigene signature based on ferroptosis-associated differentially expressed genes (DEGs). Moreover, we comprehensively analyzed the role of ferroptosis-associated miRNAs, lncRNAs, and immune responses. A total of 259 ferroptosis-related genes were extracted. KEGG function analysis of these genes revealed that they were mainly enriched in the HIF-1 signaling pathway, NOD-like receptor signaling pathway, central carbon metabolism in cancer, and PPAR signaling pathway. Fifteen differentially expressed genes (ALOX15, ALOX15B, ANO6, BRD4, CISD1, DRD5, FLT3, G6PD, IFNG, NGB, NOS2, PROM2, SLC1A4, SLC38A1, and TP63) were selected as independent prognostic factors for BC patients. Moreover, T cell functions, including the CCR score, immune checkpoint, cytolytic activity, HLA, inflammation promotion, para-inflammation, T cell co-stimulation, T cell co-inhibition, and type II INF responses were significantly different between the low-risk and high-risk groups of the TCGA cohort. Immune checkpoints between the two groups revealed that the expressions of PDCD-1 (PD-1), CTLA4, LAG3, TNFSF4/14, TNFRSF4/8/9/14/18/25, and IDO1/2 among others were significantly different. A total of 1185 ferroptosis-related lncRNAs and 219 ferroptosis-related miRNAs were also included in this study. From the online database, we identified novel ferroptosis-related biomarkers for breast cancer prognosis. The findings of this study provide new insights into the development of new reliable and accurate cancer treatment options.

SUBMITTER: Wu ZH

PROVIDER: S-EPMC8097021 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundFerroptosis is a kind of programmed cell death that is characterized by iron dependence. It differs from apoptosis, necrosis, autophagy, pyroptosis, and other types of cell death. Some studies have found that most of the genes involved in the regulation of ferroptosis or act as markers of ferroptosis are related to the poor prognosis of cancer patients.MethodsThis study evaluated the expression, mutation, and copy number variation (CNV) of 60 previously reported ferroptosis genes in breast cancer samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Unsupervised clustering of breast cancer samples with ferroptosis genes was performed, followed by enrichment analysis with Gene Set Variation Analysis (GSVA), mutation display, and correlation analysis of clinical characteristics. Based on the analysis of differences among groups, the ferroptosis-related genes were identified, and the consistent clustering of breast cancer samples was performed. The characteristic genes were screened by stochastic forest algorithm and COX analysis, and a ferroptosis score (ferr.score) model was constructed to evaluate the prognosis of breast cancer patients.ResultsCopy number amplification and deletion of ferroptosis genes are common in breast cancer. Breast cancer patients grouped by ferroptosis gene clusters showed significant differences in survival, immune cell infiltration, and enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways. The ferroptosis-related differential genes were identified by comparison among clustering groups of ferroptosis gene. Characteristic genes were screened from these ferroptosis-related differential genes to construct the ferr.score model. The scoring model could accurately distinguish and predict the survival prognosis and immunotherapy efficacy in breast cancer patients.ConclusionsFerroptosis plays an important role in the occurrence and development of tumors. According to the ferr.score model, the breast cancer samples can be divided into two groups with significantly different prognoses. These results provide novel insights and ideas for immunotherapy in breast cancer patients.

Project description:BackgroundFerroptosis is a novel iron-dependent form of cell death, which is implicated in various diseases including cancers. However, the influence of ferroptosis-related genes on the prognosis of breast cancer remains unclear.MethodsRNA sequencing data of 1053 breast cancer tissue samples and 111 normal tissue samples from The Cancer Genome Atlas (TCGA) were analyzed. Expression levels of 259 ferroptosis-related genes were compared. Gene Ontology (GO) and the Kyoto Gene and Genomic Encyclopedia (KEGG) analyses were conducted on differentially expressed genes. Cox univariate analysis was conducted to explore the potential prognostic biomarkers of breast cancer. Infiltrating immune cell status was assessed.ResultsA total of 66 ferroptosis-related genes were differentially expressed in breast cancer tissues. The enriched GO terms included Biological Process (mainly included response to oxidative stress, cellular response to chemical stress, multicellular organismal homeostasis, cofactor metabolic process, response to metal ion, response to steroid hormone, cellular response to oxidative stress, transition metal ion homeostasis, iron ion homeostasis, and cellular iron ion homeostasis), Cellular Component (mainly included apical plasma membrane, early endosome, apical part of cell, lipid droplet, basolateral plasma membrane, blood microparticle, clathrin-coated pit, caveola, astrocyte projection, and pronucleus) and Molecular Function (mainly included iron ion binding, ubiquitin protein ligase binding, oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor, ferric iron binding, aldo-keto reductase (NADP) activity, oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, steroid dehydrogenase activity, alditol:NADP+1-oxidoreductase activity, and alcohol dehydrogenase (NADP+) activity). The enriched KEGG pathway mainly included the HIF-1 signaling pathway, NOD-like receptor signaling pathway, ferroptosis, IL-17 signaling pathway, central carbon metabolism in cancer, PPAR signaling pathway, PD-L1 expression, and PD-1 checkpoint pathway in cancer. Among them, 38 ferroptosis-related genes were significantly associated with the prognosis of breast cancer. The prognostic model was constructed, and breast cancer patients in low-risk group had a better prognosis. In addition, risk score of ferroptosis prognostic model was negatively correlated with B cells (r = -0.063, p = 0.049), CD8+ T cells (r = -0.083, p = 0.010), CD4+ T cells (r = -0.097, p = 0.002), neutrophils (r = -0.068, p = 0.033), and dendritic cells (r = 0.088, p = 0.006).ConclusionsThe ferroptosis pathway plays a key role in breast cancer. Some differentially expressed ferroptosis-related genes can be used as prognostic biomarkers for breast cancer.

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The role of ferroptosis in breast cancer patients: a comprehensive analysis.

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