Abstract
Background: Triple-negative breast cancer (TNBC) is the most invasive and metastatic subtype of breast cancer. SUMO1-activating enzyme subunit 1 (SAE1), an E1-activating enzyme, is indispensable for protein SUMOylation. SAE1 has been found to be a relevant biomarker for progression and prognosis in several tumor types. However, the role of SAE1 in TNBC remains to be elucidated.Methods: In the research, the mRNA expression of SAE1 was analyzed via the cancer genome atlas (TCGA) and gene expression omnibus (GEO) database. Cistrome DB Toolkit was used to predict which transcription factors (TFs) are most likely to increase SAE1 expression in TNBC. The correlation between the expression of SAE1 and the methylation of SAE1 or quantity of tumor-infiltrating immune cells was further invested. Single-cell analysis, using CancerSEA, was performed to query which functional states are associated with SAE1 in different cancers in breast cancer at the single-cell level. Next, weighted gene coexpression network (WGCNA) was applied to reveal the highly correlated genes and coexpression networks of SAE1 in TNBC patients, and a prognostic model containing SAE1 and correlated genes was constructed. Finally, we also examined SAE1 protein expression of 207 TNBC tissues using immunohistochemical (IHC) staining.Results: The mRNA and protein expression of SAE1 were increased in TNBC tissues compared with adjacent normal tissues, and the protein expression of SAE1 was significantly associated with overall survival (OS) and disease-free survival (DFS). Correlation analyses revealed that SAE1 expression was positively correlated with forkhead box M1 (FOXM1) TFs and negatively correlated with SAE1 methylation site (cg14042711) level. WGCNA indicated that the genes coexpressed with SAE1 belonged to the green module containing 1,176 genes. Through pathway enrichment analysis of the module, 1,176 genes were found enriched in cell cycle and DNA repair. Single-cell analysis indicated that SAE1 and its coexpression genes were associated with cell cycle, DNA damage, DNA repair, and cell proliferation. Using the LASSO COX regression, a prognostic model including SAE1 and polo-like kinase 1 (PLK1) was built to accurately predict the likelihood of DFS in TNBC patients.Conclusion: In conclusion, we comprehensively analyzed the mRNA and protein expression, prognosis, and interaction genes of SAE1 in TNBC and constructed a prognostic model including SAE1 and PLK1. These results might be important for better understanding of the role of SAE1 in TNBC. In addition, DNA methyltransferase and TFs inhibitor treatments targeting SAE1 might improve the survival of TNBC patients.
Highlights
Triple-negative breast cancer (TNBC) is a specific type of breast cancer which lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2) (Jhan and Andrechek, 2017; Vagia et al, 2020)
We found that the average mRNA expression of SAE1 was higher in TNBC patients compared with luminal A or luminal B breast cancer subtypes based on gene expression omnibus (GEO) database GSE31448, GSE45827, and GSE65216 (Supplementary Figure 1)
Results indicated that these 11 genes including SAE1 and 10 overlap genes were positively correlated with cell cycle, DNA repair, DNA damage, and proliferation. This is consistent with contemporary knowledge that SUMOs such as SAE1 are essential for the regulation of several cellular processes, including transcriptional regulation, transcript processing, genomic replication, and DNA damage repair (Sacher et al, 2006; Hang et al, 2011; Psakhye and Jentsch, 2012; Sarangi et al, 2014; Schimmel et al, 2014; Sarangi and Zhao, 2015). The expressions of these 10 genes were further examined by survival analysis, and the results indicated that SAE1, apolipoprotein O (APOO), maintenance complex component 5 (MCM5), PHF19, polo-like kinase 1 (PLK1), and ubiquitinconjugating enzyme E2S (UBE2S) were significantly correlated with the prognosis
Summary
Triple-negative breast cancer (TNBC) is a specific type of breast cancer which lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2) (Jhan and Andrechek, 2017; Vagia et al, 2020). TNBC only comprises approximately 15–20% of all breast cancers, it has a higher recurrence and mortality rate than other types of breast cancer (Sporikova et al, 2018; da Silva et al, 2020). Patients with TNBC generally develop distant metastasis within the first 3 years after initial treatment, with the mortality rate could reach about 40% in the first 5 years (Wilson et al, 2019; Chang-Qing et al, 2020). A combination of surgery, chemotherapy, and radiotherapy remains the most common treatment strategy for TNBC patients. While significant advances have been made in the treatment of TNBC, the prognosis of these patients remains extremely poor. The role of SAE1 in TNBC remains to be elucidated
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