Abstract
To investigate the relationship between non-coding RNAs [especially circular RNAs (circRNAs)] and docetaxel resistance in breast cancer, and to find potential predictive biomarkers for taxane-containing therapies, we have performed transcriptome and microRNA (miRNA) sequencing for two established docetaxel-resistant breast cancer (DRBC) cell lines and their docetaxel-sensitive parental cell lines. Our analyses revealed differences between circRNA signatures in the docetaxel-resistant and -sensitive breast cancer cells, and discovered circRNAs generated by multidrug-resistance genes in taxane-resistant cancer cells. In DRBC cells, circABCB1 was identified and validated as a circRNA that is strongly up-regulated, whereas circEPHA3.1 and circEPHA3.2 are strongly down-regulated. Furthermore, we investigated the potential functions of these circRNAs by bioinformatics analysis, and miRNA analysis was performed to uncover potential interactions between circRNAs and miRNAs. Our data showed that circABCB1, circEPHA3.1 and circEPHA3.2 may sponge up eight significantly differentially expressed miRNAs that are associated with chemotherapy and contribute to docetaxel resistance via the PI3K-Akt and AGE-RAGE signaling pathways. We also integrated differential expression data of mRNA, long non-coding RNA, circRNA, and miRNA to gain a global profile of multi-level RNA changes in DRBC cells, and compared them with changes in DNA copy numbers in the same cell lines. We found that Chromosome 7 q21.12-q21.2 was a common region dominated by multi-level RNA overexpression and DNA amplification, indicating that overexpression of the RNA molecules transcribed from this region may result from DNA amplification during stepwise exposure to docetaxel. These findings may help to further our understanding of the mechanisms underlying docetaxel resistance in breast cancer.
Highlights
Breast cancer is the most prevalent and mortal cancer among women worldwide [1]
We identified expressed circABCB1 in docetaxel-resistant breast cancer cells, and the qPCR experiment confirmed the overexpression of circABCB1 in docetaxel-resistant breast cancer cells in comparison to the sensitive parental cells, which indicated that the expression of circABCB1 in docetaxel-resistant breast cancer cells may has been caused by the amplification of ABCB1 gene
Accumulating evidence has shown that the circRNA-miRNA-mRNA axis plays important regulatory roles in the development of different types of cancer [22, 58]
Summary
Chemotherapy is a very important treatment for breast cancer, especially for hormone-insensitive, advanced or metastatic breast cancer. The taxane class of chemotherapy agents, including docetaxel and paclitaxel, were introduced into the treatment of advanced breast cancer about two decades ago and recognized as a significant improvement for breast cancer treatment [2]. Docetaxel is a semisynthetic derivative of paclitaxel, and regarded as a second-generation taxane [4]. Taxane-containing treatment regimens have been shown to improve overall survival in both early-stage and advanced breast cancer when compared with non-taxane regimens [8, 9]. Either alone or in combination, are commonly applied as first-line treatments for advanced breast cancer [10]. No biomarkers have been successfully identified for response to taxanes in clinical treatments of breast cancer
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