Abstract
Resistance to adjuvant systemic treatment, including taxanes (docetaxel and paclitaxel) is a major clinical problem for breast cancer patients. lncRNAs (long non-coding RNAs) are non-coding transcripts, which have recently emerged as important players in a variety of biological processes, including cancer development and chemotherapy resistance. However, the contribution of lncRNAs to docetaxel resistance in breast cancer and the relationship between lncRNAs and taxane-resistance genes are still unclear. Here, we performed comprehensive RNA sequencing and analyses on two docetaxel-resistant breast cancer cell lines (MCF7-RES and MDA-RES) and their docetaxel-sensitive parental cell lines. We identified protein coding genes and pathways that may contribute to docetaxel resistance. More importantly, we identified lncRNAs that were consistently up-regulated or down-regulated in both the MCF7-RES and MDA-RES cells. The co-expression network and location analyses pinpointed four overexpressed lncRNAs located within or near the ABCB1 (ATP-binding cassette subfamily B member 1) locus, which might up-regulate the expression of ABCB1. We also identified the lncRNA EPB41L4A-AS2 (EPB41L4A Antisense RNA 2) as a potential biomarker for docetaxel sensitivity. These findings have improved our understanding of the mechanisms underlying docetaxel resistance in breast cancer and have provided potential biomarkers to predict the response to docetaxel in breast cancer patients.
Highlights
Breast cancer is the most frequently diagnosed cancer among females and the leading cause of cancer death among women worldwide[1]
Taxanes are a class of anti-microtubule agents that have been demonstrated to be more efficient than anthracycline-based regimens and are listed as the first-line regimens for breast cancer[28,29]
A number of genes were identified to be associated with taxane resistance, and the differential expression of the ABCB1 gene was extensively investigated and identified as one of the most credible biomarkers in chemotherapy-resistant cancers[3,4,33,34,36,37]
Summary
Breast cancer is the most frequently diagnosed cancer among females and the leading cause of cancer death among women worldwide[1]. The differential expression of the ABCB1 gene is one of the most studied putative biomarkers in taxane-resistant cancers[3,4]. Pgp (permeability glycoprotein), encoded by the ABCB1 gene, has been reported to act as an ATP-dependent efflux pump and reduce taxane concentration by expelling the drug[5]. From a transcriptome microarray study, the lncRNAs HIF1A-AS2 (HIF1A Antisense RNA 2) and AK124454 were shown to promote cell proliferation and invasion in TNBC (triple-negative breast cancers) cells and contribute to paclitaxel resistance[13]. We identified significantly differentially expressed (SDE) mRNAs and lncRNAs between the parental and resistant sublines, and we uncovered the potential relationship between the SDE mRNAs and lncRNAs. Compared with previous studies, we discovered several novel genes in addition to ABCB1 which might contribute to the taxane-resistant phenotype of breast cancers. We identified a group of lncRNAs that might potentially regulate taxane sensitivity by controlling the expression of chemotherapy-resistant genes
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