Identification of key genes controlling breast cancer stem cell characteristics via stemness indices analysis

Jianying Pei,Yan Li,Yanxia Wang

doi:10.1186/s12967-020-02260-9

Abstract

BackgroundWith the gradual unveiling of tumour heterogeneity, cancer stem cells (CSCs) are now being considered the initial component of tumour initiation. However, the mechanisms of the growth and maintenance of breast cancer (BRCA) stem cells are still unknown.MethodsTo explore the crucial genes modulating BRCA stemness characteristics, we combined the gene expression value and mRNA expression-based stemness index (mRNAsi) of samples from The Cancer Genome Atlas (TCGA), and the mRNAsi was corrected using the tumour purity (corrected mRNAsi). mRNAsi and corrected mRNAsi were analysed and showed a close relationship with BRCA clinical characteristics, including tumour depth, pathological staging and survival status. Next, weighted gene co-expression network analysis (WGCNA) was applied to distinguish crucial gene modules and key genes. A series of functional analyses and expression validation of key genes were conducted using multiple databases, including Oncomine, Gene Expression Omnibus (GEO) and Gene Expression Profiling Integrative Analysis (GEPIA).ResultsThis study found that mRNAsi and corrected mRNAsi scores were higher in BRCA tissues than that in normal tissues, and both of them increased with tumour stage. Higher corrected mRNAsi scores showed worse overall survival outcomes. We screened 3 modules and 32 key genes, and those key genes were found to be strongly correlated with each other. Functional analysis revealed that the key genes were related to cell fate decision events such as the cell cycle, cellular senescence, chromosome segregation and mitotic nuclear division. Among 32 key genes, we identified 12 genes that strongly correlated with BRCA survival.ConclusionsThirty-two genes were found to be closely related to BRCA stem cell characteristics; among them, 12 genes showed prognosis-oriented effects in BRCA patients. The most significant signalling pathway related to stemness in BRCA was the cell cycle pathway, which may support new ideas for screening therapeutic targets to inhibit BRCA stem characteristics. These findings may highlight some therapeutic targets for inhibiting BRCA stem cells.

Highlights

With the gradual unveiling of tumour heterogeneity, cancer stem cells (CSCs) are being considered the initial component of tumour initiation
Results mRNA expression-based stemness index (mRNAsi) and corrected mRNAsi according to clinical characteristics of BRCAmRNAsi is a novel stemness index for evaluating the dedifferentiation potential of tumour cells and is considered a marker of CSCs
We found that the mRNAsi in breast cancer (BRCA) tissues was significantly higher than that in normal tissues (Fig. 1a)

Summary

Introduction

With the gradual unveiling of tumour heterogeneity, cancer stem cells (CSCs) are being considered the initial component of tumour initiation. The mechanisms of the growth and maintenance of breast cancer (BRCA) stem cells are still unknown. Breast cancer is one of the most common and lethal cancers in women. The incidence rates of breast cancer increased slightly from 2006 to 2015 and this change is considered to be caused by the prevalence of obesity and decrease in parity in women [2]. The most crucial problem in the clinical treatment of breast cancer is that most people first diagnosed with breast cancer are often in an advanced stage because of the lack of access to sensitive markers and effective therapy. It is critical for us to precisely understand the molecular mechanism underlying this complicated malignancy, which could be beneficial for discovering valuable biomarkers to diagnose or predict clinical outcomes

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