RESEARCH ARTICLE A Critical Dose of Doxorubicin Is Required to Alter the Gene Expression Profiles in MCF-7 Cells Acquiring Multidrug Resistance

Cellular mechanisms of multidrug resistance (MDR) are related to ABC transporters, apo-ptosis, antioxidation, drug metabolism, DNA repair and cell proliferation. It remains unclear whether the process of resistance development is programmable. We aimed to study gene expression profiling circumstances in MCF-7 during MDR development. Eleven MCF-7 sub-lines with incremental doxorubicin resistance were established as a valued tool to study re-sistance progression. MDRmarker P-gp was overexpressed only in cells termed MCF-7/ ADR-1024 under the selection dose approaching 1024 nM. MCF-7/ADR-1024 and authen-tic MCF-7/ADR shared common features in cell morphology and DNA ploidy status. MCF-7/ ADR-1024 and authentic MCF-7/ADR down regulated repair genes BRCA1/2 and wild type p53, apoptosis-related gene Bcl-2 and epithelial-mesenchymal transition (EMT) epithelial marker gene E-cadherin. While detoxifying enzymes glutathione-S transferase-π and pro-tein kinase C-α were up-regulated. The genes involving in EMT mesenchymal formation were also overexpressed, including N-cadherin, vimentin and the E-cadherin transcription reppressors Slug, Twist and ZEB1/2. PI3K/AKT inhibitor wortmannin suppressed expres