Coexpression Network Analysis of Genes Related to the Characteristics of Tumor Stemness in Triple-Negative Breast Cancer

Abstract

Cancer stem cells (CSCs) are subsets of cells with the ability of self-renewal and differentiation in neoplasm, which are considered to be related to tumor heterogeneity. It has been reported that CSCs act on tumorigenesis and tumor biology of triple-negative breast cancer (TNBC). However, the key genes that cause TNBC showing stem cell characteristics are still unclear. We combined the RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA) database and mRNA expression-based stemness index (mRNAsi) to further analyze mRNAsi with regard to molecular subtypes, tumor depth, and pathological staging characteristics of breast cancer (BC). Secondly, we extract the differential gene expression of tumor vs. normal group and TNBC vs. other subtypes of BC group, respectively, and intersect them to achieve precise results. We used a weighted gene coexpression network analysis (WGCNA) to screen significant gene modules and the functions of selected genes including BIRC5, CDC25A, KIF18B, KIF2C, ORC1, RAD54L, and TPX2 were carried out through gene ontology (GO) functional annotation. The Oncomine, bc-GenExMiner v4.4, GeneMANIA, Kaplan-Meier Plotter (KM-plotter), and GEPIA were used to verify the expression level and functions of key genes. In this study, we found that TNBC had the highest stem cell characteristics in BC compared with other subtypes. The lower the mRNAsi score, the better the overall survival and treatment outcome. Seven key genes of TNBC were screened and functional annotation indicated that there were strong correlations between them, relating to nuclear division, organelle fission, mitotic nuclear division, and other events that determine cell fate. Among these genes, we found four genes that were highly associated with adverse survival events. Seven key genes identified in this study were found to be closely related to the maintenance of TNBC stemness, and the overexpression of four showed earlier recurrence. The overall survival (OS) curves of all key genes between differential expression level crossed at around nine-year follow-up, which was consistent with the trend of the OS curve related to mRNAsi. These findings may provide new ideas for screening therapeutic targets in order to depress TNBC stemness.

Genome Instability-Derived Genes Are Novel Prognostic Biomarkers for Triple-Negative Breast Cancer

“…Functional analysis showed that these 111 genomic instability-related genes were enriched in the pathways associated with mitotic process. Dysregulation of mitotic processes can impact DNA replication involving mitotic nuclear division, nuclear division, and organelle fission, contributing to genome instability and OS of TNBC ( Chen L. et al, 2018 ; Si et al, 2020 ; Suo et al, 2020 ). For example, the feedback loop between Drp1-mediated mitochondrial fission and Notch signaling pathway can promote TNBC cell survival via increasing survivin expression ( Chen L. et al, 2018 ), and silibinin-induced mitochondrial fission can cause mitophagy preventing silibinin-induced apoptosis in TNBC ( Si et al, 2020 ).…”

Gene network analysis using SWIM reveals interplay between the transcription factor‐encoding genes HMGA1, FOXM1, and MYBL2 in triple‐negative breast cancer

“…By applying another network-based approach, named weighted gene co-expression network analysis (WGCNA), other studies analyzed TCGA TNBC dataset and investigated the correlation between TNBC expression and stemness, survival, and metastasis [36,37]. In particular, the authors in [36] identified a set of relevant genes, including BIRC5, CDC25A, KIF18B, KIF2C, RAD54L, and TPX2, which play important roles in the maintenance of TNBC stemness. Interestingly, we found them as switch genes in TNBC tumors vs controls, supporting the reliability of SWIM analysis.…”

Expression and Clinical Significance of Origin Recognition Complex Family in Breast Cancer

“…Previous study showned that ORC1L was up-regulated in gliomas and promoted proliferation, migration and invasion of glioma cells through activation of ERK/JNK signaling pathway 10 . In lung cancer and triple-negative BC, ORC1L was considered as a pivotal gene for the maintenance of tumor stem cell, and its expression in lung cancer was positively correlated with tumor stage 19,20 . ORC5L and ORC6L had prognostic value in hepatocellular carcinoma 17 .…”

“…ORCs are also differentially expressed in a number of tumors, such as gliomas 10 , endometrial cancer 11 , colon cancer [12][13][14] , gastric cancer 15,16 , liver cancer 17 , esophageal cancer 18 , and lung cancer 19 . They are implicated in diverse biological processes, including cell proliferation, migration, invasion, tumor stem cell maintenance, and chemotherapy resistance [11][12][13][19][20][21][22] . ORC1L, ORC5L and ORC6L have prognostic value in gastric cancer, liver cancer and colorectal cancer [14][15][16][17] .…”