Copy number variations of stepwise-selected doxorubicin-resistant MCF-7 cell lines.

Abstract

Elimination of cytotoxic effect in cells with multidrug resistance (MDR) phenotype is a situation that is gradually acquired over time and develops through multiple pathways resulting in global phenotypic changes of cells. Although molecular background of the resistance phenotype has widely been studied in the gene expression level, segmental and gene copy number variations (CNVs) have limitedly been documented. Thus, in the present study, we aimed to analyze the CNVs using DNA microarray in the sensitive and two doxorubicin-resistant MCF-7 breast cancer cell lines which had different resistance indices. In the present study, we performed conventional karyotyping and array comparative genomic hybridization (aCGH). Then, results of aCGH data were studied with genomic profiling, comparison analysis and ideogram plotting to evaluate genomic profiles, and the loss and gains of heterozygosity profiles. Next, gene lists for each cell line were compared with the 66-breast cancer-related genes and the multidrug resistance-related genes. aCGH analyses showed that CNV profiles and the copy number of specific genes were dramatically different between these three cell lines. Totally, 6212, 6558, and 11,201 genes were found to be altered in MCF-7, MCF-7/400DOX, and MCF-7/1000DOX genomes, respectively. Amongst the MCF-7/1000DOX had the highest number of altered genes, and doxorubicin resistance may cause differential chromosomal changes depending on the resistance status. DNA microarray would be one of the informative methods used in the studies on the cancer drug resistance in addition to transcriptomic and proteomic level high throughput analysis to define molecular mechanisms of the resistance status.