The role of ferroptosis‐related genes for overall survival prediction in breast cancer

Abstract

Background Ferroptosis 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. Methods RNA 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. Results A 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). Conclusions The ferroptosis pathway plays a key role in breast cancer. Some differentially expressed ferroptosis‐related genes can be used as prognostic biomarkers for breast cancer.

Heme Oxygenase Modulation Drives Ferroptosis in TNBC Cells

“…Multiple lines of evidence have suggested ferroptosis’ pivotal role in tumor suppressor pathways, including p53 activation, highlighting its relevance in the field of antineoplastic therapies [ 5 , 6 ]. Indeed, several studies have demonstrated the high potential of ferroptosis as a novel therapeutic strategy for the treatment of different cancers, including hepatic, lung and breast cancer [ 7 , 8 , 9 , 10 , 11 , 12 ]. Recent studies have confirmed that female breast cancer (BC) has overtaken lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), closely followed by lung (11.4%), colorectal (10.0%), prostate (7.3%) and stomach (5.6%) cancers.…”

Mining TCGA Database for Genes with Prognostic Value in Breast Cancer

“…GO analysis can identify gene sets enriched in any of two groups, comparing one against the other but is almost always performed between tumor and normal tissue samples in order to find biological functions altered in tumors compared to healthy tissues [ 56 , 57 , 58 ]. In order to better characterize the tumor microenvironment, we extended that use to also identify the biological functions significantly altered in PP compared to GP samples.…”

Clinical implications and immunological features of iron metabolism-related gene prognostic signature in breast cancer

“…Iron metabolism has also emerged as the possible therapeutic target and prognostic marker for breast cancer. Nowadays, the model based on ferroptosis-related genes in breast cancer has been found to be established in many studies [18][19][20], and the iron metabolism signature has been employed in lung adenocarcinoma, glioma, clear cell renal cell carcinoma, and hepatocellular carcinoma [21][22][23][24]. However, prognostic value and therapeutic importance of iron metabolismrelated genes in breast cancer remain unclear.…”

“…Therefore, targeting iron metabolism-related proteins has been developed into a promising avenue of cancer therapy, which could exert antitumor effects by enhancing antitumor immunity. Nowadays, the models based on ferroptosis-related genes in breast cancer have been established in many studies [18][19][20], and the signatures related to iron metabolism have been used in lung adenocarcinoma, glioma, renal cell carcinoma, hepatocellular carcinoma [21][22][23][24]. However, a comprehensive analysis of prognostic value and therapeutic signi cance of iron metabolism related genes in breast cancer was still unclear.…”