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Research Articles: Therapeutics, Targets, and Development

Epigenetic profiling of multidrug-resistant human MCF-7 breast adenocarcinoma cells reveals novel hyper- and hypomethylated targets

¹ Department of Mechanisms of Anticancer Therapy, R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, Kyiv, Ukraine; ² Department of Biological Sciences, University of Lethbridge, Alberta, Canada; and ³ Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas

Requests for reprints: Igor P. Pogribny, Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079. Phone: 870-543-7096; Fax: 870-543-7720. E-mail: igor.pogribny{at}fda.hhs.gov

Abstract

The successful treatment of cancer requires a clear understanding of multiple interacting factors involved in the development of drug resistance. Presently, two hypotheses, genetic and epigenetic, have been proposed to explain mechanisms of acquired cancer drug resistance. In the present study, we examined the alterations in epigenetic mechanisms in the drug-resistant MCF-7 human breast cancer cells induced by doxorubicin (DOX) and cisplatin (cisDDP), two chemotherapeutic drugs with different modes of action. Despite this difference, both of the drug-resistant cell lines displayed similar pronounced changes in the global epigenetic landscape showing loss of global DNA methylation, loss of histone H4 lysine 20 trimethylation, increased phosporylation of histone H3 serine 10, and diminished expression of Suv4-20h2 histone methyltransferase compared with parental MCF-7 cells. In addition to global epigenetic changes, the MCF-7/DOX and MCF-7/cisDDP drug-resistant cells are characterized by extensive alterations in region-specific DNA methylation, as indicated by the appearance of the number of differentially methylated DNA genes. A detailed analysis of hypo- and hypermethylated DNA sequences revealed that the acquisition of drug-resistant phenotype of MCF-7 cells to DOX and cisDDP, in addition to specific alterations induced by a particular drug only, was characterized by three major common mechanisms: dysfunction of genes involved in estrogen metabolism (sulfatase 2 and estrogen receptor ), apoptosis (p73, -tubulin, BCL2-antagonist of cell death, tissue transglutaminase 2 and forkhead box protein K1), and cell-cell contact (leptin, stromal cell–derived factor receptor 1, activin A receptor E-cadherin) and showed that two opposing hypo- and hypermethylation processes may enhance and complement each other in the disruption of these pathways. These results provided evidence that epigenetic changes are an important feature of cancer cells with acquired drug-resistant phenotype and may be a crucial contributing factor to its development. Finally, deregulation of similar pathways may explain the existence and provide mechanism of cross-resistance of cancer cells to different types of chemotherapeutic agents. [Mol Cancer Ther 2007;6(3):1089–98]

Grant support: Postgraduate Research Program given by the Oak Ridge Institute for Science and Education (V. Tryndyak) and by Alberta Breast Cancer Initiative grant (O. Kovalchuk).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: The views expressed in this paper do not necessarily represent those of the U.S. Food and Drug Administration.

⁴ Available at http://www.ncbi.nlm.nih.gov.

⁵ Available at http://www.cpgislands.com.

Received 10/26/06; revised 12/11/06; accepted 1/31/07.

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