Upregulation of the ferroptosis-related STEAP3 gene is a specific predictor of poor triple-negative breast cancer patient outcomes

Abstract

ObjectiveThis study was designed to assess ferroptosis regulator gene (FRG) expression patterns in patients with TNBC based on data derived from The Cancer Genome Atlas (TCGA). Further, it was utilized to establish a TNBC FRG signature, after which the association between this signature and the tumor immune microenvironment (TIME) composition was assessed, and relevant prognostic factors were explored.MethodsThe TCGA database was used to obtain RNA expression datasets and clinical information about 190 TNBC patients, after which a prognostic TNBC-related FRG signature was established using a least absolute shrinkage and selection operator (LASSO) Cox regression approach. These results were validated with separate data from the Gene Expression Omnibus (GEO). The TNBC-specific prognostic gene was identified via this method. The STEAP3 was then validated through Western immunoblotting, immunohistochemical staining, and quantitative real‐time polymerase chain reaction (RT-qPCR) analyses of clinical tissue samples and TNBC cell lines. Chemotherapy interactions and predicted drug sensitivity studies were investigated to learn more about the potential clinical relevance of these observations.ResultsThese data revealed that 87 FRGs were differentially expressed when comparing TNBC tumors and healthy tissue samples (87/259, 33.59%). Seven of these genes (CA9, CISD1, STEAP3, HMOX1, DUSP1, TAZ, HBA1) are significantly related to the overall survival of TNBC patients. Kaplan-Meier analyses and established FRG signatures and nomograms identified CISD1 and STEAP3 genes of prognostic relevance. Prognostic Risk Score values were positively correlated with the infiltration of CD4+ T cells (p = 0.001) and myeloid dendritic cells (p =0.004). Further evidence showed that STEAP3 was strongly and specifically associated with TNBC patient OS (P<0.05). The results above were confirmed by additional examinations of STEAP3 expression changes in TNBC patient samples and cell lines. High STEAP3 levels were negatively correlated with half-maximal inhibitory concentration (IC50) values for GSK1904529A (IGF1R inhibitor), AS601245 (JNK inhibitor), XMD8−85 (Erk5 inhibitor), Gefitinib, Sorafenib, and 5-Fluorouracil (P < 0.05) in patients with TNBC based on information derived from the TCGA-TNBC dataset.ConclusionIn the present study, a novel FRG model was developed and used to forecast the prognosis of TNBC patients accurately. Furthermore, it was discovered that STEAP3 was highly overexpressed in people with TNBC and associated with overall survival rates, laying the groundwork for the eventually targeted therapy of individuals with this form of cancer.

A critical appraisal of ferroptosis in Alzheimer’s and Parkinson’s disease: new insights into emerging mechanisms and therapeutic targets

“…CISD1-Dependent regulation of ferroptosis is shown in glutathione depletion–induced oxidative cardiomyopathy in murine hearts ( Li et al, 2024 ). CISD1 expression has been recently demonstrated as a ferroptosis hub gene of prognostic relevance for triple-negative breast cancer ( Yuan et al, 2023 ) and tumor immune filtration in gastric cancer ( Zang et al, 2023 ). NAF-1 (CISD2) is localized to the outer membrane of mitochondria, ER membrane, and mitochondrion-associated ER membranes.…”

Ferroptosis: the emerging player in remodeling triple-negative breast cancer

“…However, the study was mainly based on the existing TCGA and GEO databases, and there is a lack of external data cohorts and experimental validation, which is necessary to improve the accuracy of the model. Yuan et al constructed the expression patterns of ferroptosis-related genes and found that 7 genes, such as CA9, CISD1, STEAP3, HMOX1, DUSP1, TAZ, and HBA1, were closely related to the overall survival (OS) of TNBC (37). In particular, STEAP3 showed high expression in TNBC tissues and cells.…”

STEAP3 Affects Ovarian Cancer Progression by Regulating Ferroptosis through the p53/SLC7A11 Pathway

“…The six-transmembrane epithelial antigen of prostate 3 (STEAP3) encodes a multipass membrane metalloreductase, which can participate in Fe 3+ transport as an iron transport protein [ 12 ]. Considering the close relationship between STEAP3 and cellular iron homeostasis, its role in a variety of cancers has been extensively studied [ 13 ]. A number of studies have found that upregulation of STEAP3 is strongly associated with poor prognosis in triple-negative breast cancer as well as gliomas, suggesting that STEAP3 may be used as a specific predictor [ 13 , 14 ].…”

“…Considering the close relationship between STEAP3 and cellular iron homeostasis, its role in a variety of cancers has been extensively studied [ 13 ]. A number of studies have found that upregulation of STEAP3 is strongly associated with poor prognosis in triple-negative breast cancer as well as gliomas, suggesting that STEAP3 may be used as a specific predictor [ 13 , 14 ]. It has been also shown that STEAP3 expression is upregulated in renal cells and that it can affect the progression of renal cell carcinoma by regulating ferroptosis [ 15 ].…”