Abstract
BackgroundAcquisition of drug-resistance in cancer has led to treatment failure, however, their mechanisms have not been clarified yet. Recent observations indicated that aberrant expressed microRNA (miRNA) caused by chromosomal alterations play a critical role in the initiation and progression of cancer. Here, we performed an integrated genomic analysis combined with array-based comparative hybridization, miRNA, and gene expression microarray to elucidate the mechanism of drug-resistance.ResultsThrough genomic approaches in MCF7-ADR; a drug-resistant breast cancer cell line, our results reflect the unique features of drug-resistance, including MDR1 overexpression via genomic amplification and miRNA-mediated TP53INP1 down-regulation. Using a gain of function study with 12 miRNAs whose expressions were down-regulated and genome regions were deleted, we show that miR-505 is a novel tumor suppressive miRNA and inhibits cell proliferation by inducing apoptosis. We also find that Akt3, correlate inversely with miR-505, modulates drug sensitivity in MCF7-ADR.ConclusionThese findings indicate that various genes and miRNAs orchestrate to temper the drug-resistance in cancer cells, and thus acquisition of drug-resistance is intricately controlled by genomic status, gene and miRNA expression changes.
Highlights
Acquisition of drug-resistance in cancer has led to treatment failure, their mechanisms have not been clarified yet
These reports indicated that the emphasis on a genomic analysis was due to the fact that DNA copy number alterations are associated with expression levels of miRNAs and genes
To better understand the regulatory network underlying drug resistance in breast cancer cells, we focus on miRNAs and genes located on the genomeamplified and -deleted regions because genomic aberration is closely associated with gene expression, and this expression alteration might be constantly maintained
Summary
Acquisition of drug-resistance in cancer has led to treatment failure, their mechanisms have not been clarified yet. As reported in the studies of cancer genetics in lung, leukemia, colon, breast and ovary, a large number of miRNAs are located at chromosomal fragile sites, i.e., minimal regions of loss of heterozygosity (LOH) and minimal regions of genomic amplification [11]. These reports indicated that the emphasis on a genomic analysis was due to the fact that DNA copy number alterations are associated with expression levels of miRNAs and genes
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