A microarray analysis of differential gene expression associated with the development of doxorubicin resistance in breast carcinoma

Abstract

One of the major complications of cancer chemotherapy is the development of a multidrug resistance (MDR) phenotype. Genes known to be major contributors to this phenotype include the ABC transporter family, DNA repair class genes and phase II conjugators such as the GST family. However, though there may be predominant contribution to the MDR phenotype from one gene or family the overall phenotype probably results from the contribution of a cohort of genes, both of downstream effecter and upstream regulatory classes. Additionally, other genes differentially expressed in the MDR verses drug sensitive states may result in other phenotypic traits that may also complicate treatment, for example an increased propensity towards invasiveness. We have applied microarray analysis to breast carcinoma cells with intrinsic and acquired doxorubicin resistant phenotypes and compared the gene expression profiles obtained with each other, and with those gathered from various other drug sensitive breast carcinoma cell lines (Turton et al. 2001). The analysis has been applied at both the mRNA and genomic levels. Some expected changes in gene expression (mRNA analysis) and amplification (genomic DNA analysis) such as that for the multidrug resistance 1 (ABCB1) gene were detected. However, some unexpected associations of differential gene expression were found, some associated with known phenotypic traits, and some that may offer alternative targets for chemotherapy. The similarity of gene expression profiles between the cells with intrinsic and acquired doxorubicin resistance indicated that a tumor with an acquired doxorubicin resistant phenotype arises as a result of drug driven selection of cells with an intrinsic resistant phenotype from the majority drug sensitive population.