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Published on: September 8, 2017
miRNA-34a is associated with docetaxel resistance in human breast cancer cells
L Kastl1, I Brown, A C Schofield
1Division of Applied Medicine, School of Medicine and Dentistry, College of Life Sciences and Medicine, University of Aberdeen, Medical School, Foresterhill, Aberdeen AB25 2ZD, UK. l.kastl@dkfz-heidelberg.de
Abstract:
Docetaxel is a chemotherapy drug to treat breast cancer, however as with many chemotherapeutic drugs resistance to docetaxel occurs in 50% of patients, and the underlying molecular mechanisms of drug resistance are not fully understood. Gene regulation through microRNAs (miRNA) has been shown to play an important role in cancer drug resistance. By directly targeting mRNA, miRNAs are able to inhibit genes that are necessary for signalling pathways or drug induced apoptosis rendering cells drug resistant. This study investigated the role of differential miRNA expression in two in vitro breast cancer cell line models (MCF-7, MDA-MB-231) of acquired docetaxel resistance. MiRNA microarray analysis identified 299 and 226 miRNAs altered in MCF-7 and MDA-MB-231 docetaxel-resistant cells, respectively. Docetaxel resistance was associated with increased expression of miR-34a and miR-141 and decreased expression of miR-7, miR-16, miR-30a, miR-125a-5p, miR-126. Computational target prediction revealed eight candidate genes targeted by these miRNAs. Quantitative PCR and western analysis confirmed decreased expression of two genes, BCL-2 and CCND1, in docetaxel-resistant cells, which are both targeted by miR-34a. Modulation of miR-34a expression was correlated with BCL-2 and cyclin D1 protein expression changes and a direct interaction of miR-34a with BCL-2 was shown by luciferase assay. Inhibition of miR-34a enhanced response to docetaxel in MCF-7 docetaxel-resistant cells, whereas overexpression of miR-34a conferred resistance in MCF-7 docetaxel-sensitive cells. This study is the first to show differences in miRNA expression, in particular, increased expression of miR-34a in an acquired model of docetaxel resistance in breast cancer. This serves as a mechanism of acquired docetaxel resistance in these cells, possibly through direct interactions with BCL-2 and CCND1, therefore presenting a potential therapeutic target for the treatment of docetaxel-resistant breast cancer.
Insights
This study reveals that increased microRNA-34a (miR-34a) expression is a key factor in acquired docetaxel resistance in breast cancer cells. Modulating miR-34a levels impacts docetaxel sensitivity, suggesting it
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Docetaxel is a vital chemotherapy for breast cancer, but resistance develops in 50% of patients.
- Mechanisms of docetaxel resistance are not fully understood, hindering effective treatment.
- MicroRNAs (miRNAs) regulate gene expression and are implicated in cancer drug resistance.
Purpose of the Study:
- Investigate differential miRNA expression in acquired docetaxel-resistant breast cancer cell lines.
- Identify specific miRNAs and their target genes involved in docetaxel resistance.
- Determine the role of miR-34a in docetaxel resistance and its therapeutic potential.
Main Methods:
- Utilized miRNA microarray analysis to compare miRNA expression profiles.
- Employed computational target prediction to identify potential miRNA targets.
- Validated gene and protein expression using quantitative PCR and Western blot analysis.
- Confirmed direct miRNA-target interaction via luciferase assays.
Main Results:
- Identified 299 and 226 differentially expressed miRNAs in MCF-7 and MDA-MB-231 docetaxel-resistant cells, respectively.
- Found increased miR-34a and miR-141 expression, and decreased expression of several other miRNAs.
- Confirmed BCL-2 and CCND1 as targets of miR-34a, with decreased expression in resistant cells.
- Demonstrated that miR-34a inhibition enhances docetaxel response, while overexpression confers resistance.
Conclusions:
- Increased miR-34a expression is a novel mechanism contributing to acquired docetaxel resistance in breast cancer.
- miR-34a directly targets BCL-2 and CCND1, influencing apoptosis and cell cycle pathways.
- miR-34a represents a potential therapeutic target for overcoming docetaxel resistance in breast cancer patients.
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