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Research Articles: Therapeutics, Targets, and Development

Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin

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

Requests for reprints: Olga Kovalchuk, Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, Canada T1K 3M4. Phone: 403-394-3916. E-mail: olga.kovalchuk{at}uleth.ca; or Igor P. Pogribny, Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079. Phone: 870-543-7096. E-mail: igor.pogribny{at}fda.hhs.gov

Abstract

Many chemotherapy regiments are successfully used to treat breast cancer; however, often breast cancer cells develop drug resistance that usually leads to a relapse and worsening of prognosis. We have shown recently that epigenetic changes such as DNA methylation and histone modifications play an important role in breast cancer cell resistance to chemotherapeutic agents. Another mechanism of gene expression control is mediated via the function of small regulatory RNA, particularly microRNA (miRNA); its role in cancer cell drug resistance still remains unexplored. In the present study, we investigated the role of miRNA in the resistance of human MCF-7 breast adenocarcinoma cells to doxorubicin (DOX). Here, we for the first time show that DOX-resistant MCF-7 cells (MCF-7/DOX) exhibit a considerable dysregulation of the miRNAome profile and altered expression of miRNA processing enzymes Dicer and Argonaute 2. The mechanistic link of miRNAome deregulation and the multidrug-resistant phenotype of MCF-7/DOX cells was evidenced by a remarkable correlation between specific miRNA expression and corresponding changes in protein levels of their targets, specifically those ones that have a documented role in cancer drug resistance. Furthermore, we show that microRNA-451 regulates the expression of multidrug resistance 1 gene. More importantly, transfection of the MCF-7/DOX-resistant cells with microRNA-451 resulted in the increased sensitivity of cells to DOX, indicating that correction of altered expression of miRNA may have significant implications for therapeutic strategies aiming to overcome cancer cell resistance. [Mol Cancer Ther 2008;7(7):2152–9]

Grant support: Alberta Cancer Board, Canadian Institutes for Health Research, and National Science and Engineering Council of Canada; National Science and Engineering Council of Canada Graduate Scholarship (J. Filkowski); and Postgraduate Research Program administered by the Oak Ridge Institute for Science and Education (V. Tryndyak).

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.

⁴ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 1/ 8/08; revised 3/ 5/08; accepted 3/30/08.