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.
Highlights
Resistance of cancer cells to chemotherapy continues to be a major clinical obstacle to the successful treatment of cancer, including breast cancer (1 – 3)
The cluster analysis revealed that the MCF-7 breast cancer cells with acquired resistance to DOX were characterized by significant changes in miRNA expression
We identified 137 miRNA genes (63 up-regulated and 75 down-regulated) that were differentially expressed (P < 0.05) in the MCF-7/DOX cells compared with the parental MCF-7 cells (Supplementary Table S1)
Summary
Resistance of cancer cells to chemotherapy continues to be a major clinical obstacle to the successful treatment of cancer, including breast cancer (1 – 3). The karyotypic hypothesis [8] is closely related to the epigenetic one in view of the wellknown fact that epigenetic changes are a necessary prerequisite to karyotypic changes [9]. In this regard, karyotypic changes may be considered as a consequence of the epigenetic alterations progression and may serve as indirect evidence of the importance of epigenetic dysregulation in the acquisition of cancer drug resistance
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