Docetaxel is a chemotherapy drug used to treat breast cancer, however as with many chemotherapeutic drugs, resistance commonly occurs and the underlying molecular mechanisms of drug resistance are not fully understood. Gene regulatory mechanisms like DNA methylation, histone deacetylation and miRNA expression have been shown to play an important role in cancer drug resistance. This study investigated the role of these mechanisms in two in vitro breast cancer cell line models (MCF-7 and MDA-MB-231) of acquired docetaxel resistance. Using inhibitors to DNA methylation and histone deacetylation, response to docetaxel could be enhanced in both breast cancer cells and cDNA microarray expression analysis identified candidate genes that were re-expressed after treatment with both inhibitors, therefore being associated with docetaxel resistance. Decreased expression of one candidate gene, SERPINE1, was directly linked to docetaxel resistance whereby SERPINE1 modulation, using siRNA technology, directly altered response to docetaxel. Furthermore, miRNA expression profiling was performed in both docetaxel-sensitive and docetaxel-resistant cell lines where alterations of miRNAs were observed and associated with a docetaxel-resistant phenotype. In particular, increased expression of miR-34a was identified in docetaxel-resistant cells, which was associated with and with decreased BCL2 and cyclin D1 mRNA and protein expression in these cells. Modulation of miR-34a expression altered docetaxel response in both docetaxelsensitive and docetaxel-resistant cells, therefore identifying increased miR-34a as direct cause of docetaxel resistance in these cells. In addition, miR-34a was shown to directly target BCL2, which may present a mechanism through which miR-34a mediates docetaxel resistance. Overall, this study identified alterations in DNA methylation, histone deacetylation and miRNA expression as mechanisms through which gene expression is altered in docetaxel-resistant breast cancer cells.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:531870 |
| Date | January 2007 |
| Creators | Kastl, Lena |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=158488 |
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