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Greater Sudbury, Canada

Reed K.,Laurentian University | Reed K.,Tumour Biology Research Program | Parissenti A.M.,Laurentian University | Parissenti A.M.,Tumour Biology Research Program | Parissenti A.M.,University of Ottawa
Current Pharmacogenomics and Personalized Medicine | Year: 2010

While the role of accumulations of mutations has been historically emphasized in the etiology of human cancers, converging evidence strongly implicates contributory epigenetic mechanisms as well. Recently, there have been accumulating observations on the role which epigenetics plays in the regulation of ABCB1 drug transporter expression and its ability to contribute to cancer incidence and multi-drug resistance (MDR) to a wide variety of therapeutic agents. As the development and use of epigenetic therapies for the prevention and treatment of cancer increase, the effect of these interventions on ABCB1 expression (and the related development of MDR) needs to be addressed. The potential for such agents and chemotherapy drugs to induce ABCB1 expression and drug resistance within the cancers they are attempting to treat or prevent is high. Thus, monitoring ABCB1 promoter methylation may be of particular importance when chemotherapy and epigenetic therapies are used, in particular if such agents induce ABCB1 expression. This information could improve our ability to distinguish between drug-sensitive tumours and MDR tumours. In addition, monitoring epigenetic changes within the promoters of ABCB1 and other genes implicated in chemotherapy resistance could help guide patient management by epigenetic agents and/or chemotherapy. The potential for monitoring dynamic changes in promoter methylation for genes associated with drug response using blood samples, rather than tumour core biopsies from cancer patients, makes this an extremely attractive approach for pharmacoepigenomics applications in the clinic. © 2010 Bentham Science Publishers Ltd. Source


Reed K.,Laurentian University | Reed K.,Tumour Biology Research Program | Hembruff S.L.,Tumour Biology Research Program | Sprowl J.A.,Laurentian University | And 3 more authors.
Pharmacogenomics Journal | Year: 2010

Induced expression of the Abcb1 drug transporter often occurs in tumors in response to chemotherapy. The role that epigenetic modifications within the ABCB1 promoter play in Abcb1 expression remains unclear. We selected MCF-7 cells for survival in increasing doses of chemotherapy drugs, and assessed the methylation status of 66 CpG sites within the ABCB1 promoter preceding, accompanying and following the onset of drug resistance. Increased ABCB1 transcript expression coincident with acquisition of resistance to epirubicin or paclitaxel was temporally associated with hypomethylation of the ABCB1 downstream promoter in the absence of gene amplifications or changes in mRNA stability. Treatment of control MCF-7 cells with demethylating and/or acetylating agents increased ABCB1 transcript expression. In addition to broad promoter hypomethylation, dramatic reductions in the methylation of specific CpG sites within the promoter were observed, suggesting that these sites may play a predominant role in transcriptional activation through promoter hypomethylation. Furthermore, our data suggest that allele-specific reductions in ABCB1 promoter methylation regulate promoter usage within paclitaxel-resistant cells. This study provides strong evidence that changes in ABCB1 promoter methylation, ABCB1 promoter usage and ABCB1 transcript expression can be temporally and causally correlated with the acquisition of drug resistance in breast tumor cells. © 2010 Macmillan Publishers Limited. All rights reserved. Source

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