Dysregulated lncRNA-miRNA-mRNA Network Reveals Patient Survival-Associated Modules and RNA Binding Proteins in Invasive Breast Carcinoma.

Yu Dong,Chunjie Jiang,Qihui Shi,Yang Xiao

doi:10.3389/fgene.2019.01284

Yu Dong, Chunjie Jiang + Show 2 more

Open Access

https://doi.org/10.3389/fgene.2019.01284

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Abstract

Breast cancer is the most common cancer in women, but few biomarkers are effective in clinic. Previous studies have shown the important roles of non-coding RNAs in diagnosis, prognosis, and therapy selection for breast cancer and have suggested the significance of integrating molecules at different levels to interpret the mechanism of breast cancer. Here, we collected transcriptome data including long non-coding RNA (lncRNA), microRNA (miRNA), and mRNA for ~1,200 samples, including 1079 invasive breast carcinoma samples and 104 normal samples, from The Cancer Genome Atlas (TCGA) project. We identified differentially expressed lncRNAs, miRNAs, and mRNAs that distinguished invasive carcinoma samples from normal samples. We further constructed an integrated dysregulated network consisting of differentially expressed lncRNAs, miRNAs, and mRNAs and found housekeeping and cancer-related functions. Moreover, 58 RNA binding proteins (RBPs) involved in biological processes that are essential to maintain cell survival were found in the dysregulated network, and 10 were correlated with overall survival. In addition, we identified two modules that stratify patients into high- and low-risk subgroups. The expression patterns of these two modules were significantly different in invasive carcinoma versus normal samples, and some molecules were high-confidence biomarkers of breast cancer. Together, these data demonstrated an important clinical application for improving outcome prediction for invasive breast cancers.

Highlights

In women, breast cancer is the most commonly diagnosed cancer and accounts for ~30% of new cancer diagnoses (Siegel et al, 2017)
4269 protein-coding genes that were differentially expressed between invasive breast carcinoma and normal samples were identified, including 2349 up-regulated and 1920 down-regulated genes (Tables S2 and S3)
It has been reported that long non-coding RNA (lncRNA) and miRNAs play important roles in breast cancer, as do protein-coding genes (Cizkova et al, 2013; Li et al, 2014b; Kim et al, 2015; Yang et al, 2018b)

Summary

Introduction

Breast cancer is the most commonly diagnosed cancer and accounts for ~30% of new cancer diagnoses (Siegel et al, 2017). Invasive breast carcinoma accounts for about 80% of breast cancer (Weigelt et al, 2008) and exhibits high heterogeneity in terms of morphology, clinical features, and prognosis (Milanovic et al, 2013), and the regulatory mechanisms at the genomic level still need to be unearthed. The lncRNA DSCAM-AS1 holds a central position in estrogen receptor (ER)-regulated breast cancer and modulates tamoxifen resistance and tumor progression (Niknafs et al, 2016). Another lncRNA, MAGI2AS3, can target the Fas/FasL signaling pathway to suppress cell growth in breast cancer (Yang et al, 2018b). The above results imply the significance of integrating molecules at different regulatory levels for interpreting the mechanism of breast cancer, especially in invasive breast carcinoma

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