Ferroptosis regulators, especially SQLE, play an important role in prognosis, progression and immune environment of breast cancer

Abstract

Background Ferroptosis, a new form of programmed cell death, has great potential for cancer treatment. However, the roles of ferroptosis-related (FR) genes in breast cancer (BC) remain elusive. Materials and methods Using TCGA database, a novel FR risk signature was constructed through the Lasso regression analysis. Meanwhile, its prognostic value was assessed by a series of survival analyses. Besides, a nomogram was constructed to predict the overall survival rate (OSR) of individual at 1,3,5 year. Four validation cohorts (n = 2248), including METABRIC, GSE58812, GSE20685 and ICGC-KR datasets, were employed to test the prognostic value of FR risk signature. The effects of FR risk signature on BC immune microenvironment were explored by CIBERSORT algorithm and ssGSEA method. The histological expressions of FR risk genes were presented by HPA database. The biofunctions of SQLE were determined by qPCR, MTT, wound-healing and Transwell assays. Results We constructed a novel FR risk signature consisting of eight genes. High FR risk led a poor prognosis and was identified as an independent prognostic factor. Besides, A higher proportion of patients with luminal A type was observed in low-risk group (53%), while a higher proportion of patients with basal type in high-risk group (24%). FR risk score could discriminate the prognostic difference of most clinical subgroups, except for M1 stage, HER2 and basal types. Moreover, its prognostic value was successfully validated in other four cohorts. Through immune analyses, we found that the reduced infiltration levels of CD8+ and NK cells, whereas the enhanced activity of antigen presentation process appeared in high FR risk. Then, FR risk score was found to weakly correlate with the expressions of six immune checkpoints. Through the experiments in vitro, we confirmed that overexpression of SQLE could promote, whereas blocking SQLE could inhibit the proliferative, migrative and invasive abilities of BC cells. Conclusions FR risk signature was conducive to BC prognostic assessment. High FR risk level was closely associated with BC immunosuppression, but may not predict ICIs efficacy. Moreover, SQLE was identified as a crucial cancer-promoting gene in BC. Our findings provide new insights into prognostic assessment and molecular mechanism of BC.

CanSig: discovery of shared transcriptional states across cancer patients from single-cell RNA sequencing data

“…Some of the strongest gains in 8q included PHF20L1, NRDG1, MYC and SQLE . In the context of breast cancer, PHF20L1 overexpression promotes tumorigenesis and is associated with higher grades 54 , NRDG1 overexpression is associated with metastasis and mortality 55 , MYC is a classical amplified oncogene 56 and SQLE overexpression promoted proliferation and invasiveness 57 . The luminal B subtype is an aggressive breast cancer subtype, thus consistent with these amplifications 58 .…”

Downregulated ferroptosis‐related gene SQLE facilitates temozolomide chemoresistance, and invasion and affects immune regulation in glioblastoma

“…SQLE is the key rate‐limiting enzyme in cholesterol biosynthesis and a target of fungicides and increasing interest in human health and disease 16 . Previous studies revealed that, as a ferroptosis regulator, SQLE was associated with the proliferation and metastasis of breast cancer 19 . Tumor‐related genes usually show two sides, inhibiting or promoting cancer.…”

“…Recently, human SQLE has attracted more and more attention as a bonafide oncogene and a target of tumor treatment 17,18 . As a ferroptosis regulator, SQLE was identified as a crucial cancer‐promoting gene in the breast cancer 19 . Moreover, previous studies indicated that SQLE reduction disrupted the GSK3β/p53 complex, and helped colorectal tumor cells surmount constraints by evoking the epithelial‐mesenchymal transition (EMT) process required to produce tumor stem cells 20 .…”

“… 17 , 18 As a ferroptosis regulator, SQLE was identified as a crucial cancer‐promoting gene in the breast cancer. 19 Moreover, previous studies indicated that SQLE reduction disrupted the GSK3β/p53 complex, and helped colorectal tumor cells surmount constraints by evoking the epithelial‐mesenchymal transition (EMT) process required to produce tumor stem cells. 20 Cancer stem cells possess the properties of self‐renewal and drug resistance and are closely linked to tumor metastasis and drug recurrence.…”

Development and validation of a novel 3-gene prognostic model for pancreatic adenocarcinoma based on ferroptosis-related genes

“…Previous studies have demonstrated that infiltrating immune cells can be isolated from tumors suggesting that tumor immune infiltration is a crucial biological process of cancers [ 10 ]. Further, many studies indicate that ferroptosis regulators play an important role in immune environment of cancers including breast cancer [ 11 ], hepatocellular carcinoma [ 12 ], and others. However, the ferroptosis related genes of tumor immune infiltration in PAAD remain largely unknown.…”