Abstract
Increasing evidence has revealed close relationships between long non-coding RNAs (lncRNAs) and chemoresistance in multiple types of tumors; however, functional lncRNAs in breast cancer (BC) have not been completely identified. In this study, we aimed to identify novel lncRNAs that might play critical roles in doxorubicn resistance, which could reveal potential biomarkers of BC. Using a BC dataset (GSE81971), we identified 452 lncRNAs that were upregulated and 659 that were downregulated; furthermore, there were 1896 differentially expressed mRNAs, of which 1137 were upregulated and 758 were downregulated in MCF-7/ADR cells compared with the expression in MCF-7 cells. We constructed an lncRNA–mRNA network by integrating probe reannotation and regulatory interactions. To elucidate the key lncRNAs in BC, we further analyzed dysregulated lncRNA–mRNA crosstalk, and six candidate lncRNAs (lnc-TRDMT1-5, ZNF667-AS1, lnc-MPPE1-13, DSCAM-AS1:5, DSCAM-AS1:2, and lnc-CFI-3) were identified. Notably, the expression level of lnc-TRDMT1-5 was significantly upregulated in resistant cells compared with sensitive cells, and its levels were increased in BC tissues compared with adjacent tissues. Levels were positively associated with estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) expression levels. High expression of lnc-TRDMT1-5 predicted poor prognosis in ER-positve and HER2-positive BC patients, especially in patients with chemoresistance. Bioinformatic and functional analysis revealed that lnc-TRDMT1-5 was involved in many crucial pathways in cancer, such as the PI3K/AKT and Wnt signaling pathways. Subcellular localization predicted that lnc-TRDMT1-5 was located in the cytoplasm, and the lncRNA–miRNA–mRNA network showed that lnc-TRDMT1-5 might serve as a regulator in BC. Here, our results demonstrated a dysregulated lncRNA–mRNA network that might provide new treatment strategies for chemoresistant BC, and the results identified a new lncRNA, lnc-TRDMT1-5, with oncogenic and prognostic functions in human BC.
Highlights
Breast cancer (BC) is one of the most commonly diagnosed cancers among women (Siegel et al, 2017)
Unlike their approach in choosing the top DE-long non-coding RNAs (lncRNAs), we looked for functional mRNAs that overlapped in the GO and pathway enrichment analyses to find the correlated lncRNAs, despite the marked alteration in a large number of DE-lncRNAs and DE-mRNAs
The lncRNA-mRNA coexpression network we constructed clearly revealed that some crucial lncRNAs and mRNAs act as important regulators in a wide range of biological functions, and it provided a new view of potential lncRNAs involved in breast cancer (BC) chemoresistance
Summary
Breast cancer (BC) is one of the most commonly diagnosed cancers among women (Siegel et al, 2017). Studies have revealed that long noncoding RNAs (lncRNAs) are involved in multiple biological processes in the regulation of gene expression, including transcriptional, and posttranscriptional regulation, enabling them to play crucial roles in cancer metastasis and to increase chemoresistance (Xue et al, 2016) and rates of poor prognois (Tordonato et al, 2015). It is important to study the functional lncRNAs related to chemoresistance and prognosis in BC. It is thought that the lncRNA– mRNA network provides a different approach to study the function of lncRNAs in cancer development (Liu et al, 2015; Schmitt and Chang, 2016). Specific functional lncRNAs, as well as their underlying activity in DOXresistant BC, remain to be further characterized
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