ORIGINAL ARTICLE Gene expression analysis of drug-resistant MCF-7 cells: implications for relation to extracellular matrix proteins O ¨ zlem Darcansoy Is ¸eri Æ Meltem Demirel Kars Æ Fikret Arpaci Æ Ufuk Gu ¨ndu ¨z Received: 25 April 2009 / Accepted: 29 May 2009 / Published online: 19 June 2009 Ó Springer-Verlag 2009 Abstract Purpose Since multidrug resistance is a multifactorial phenomenon, a large-scale expression analysis of drug- resistant cells by using high-density oligonucleotide microarrays may provide information about new candidate genes contributing to resistance. Extracellular matrix (ECM) is responsible for many aspects of proliferation and invasive/metastatic behavior of tumor cells. This study demonstrates alterations in gene expression levels of sev- eral ECM components, matrix metalloproteinases (MMPs), adamalysins (ADAMs and ADAMTSs) and tissue inhibi- tors of metalloproteinases (TIMPs) in paclitaxel, docetaxel, vincristine and doxorubicin-resistant MCF-7 cells. Methods Resistant MCF-7 cells were developed by stepwise selection of cells in increasing concentrations of drugs. Affymetrix GeneChip Ò Human Genome U133 Plus 2.0 Array was used for hybridizations. Statistical signifi- cance was determined by independent sample t test. The genes having altered expression levels in drug-resistant sublines were selected and filtered by volcano plots. Results Genes up/downregulated more than twofolds were selected and listed. Expression of 25 genes encoding ECM proteins (including collagen, finronectin and synd- ecan) and integrin receptor subunits were found to be upregulated in drug-resistant cells. In addition, expression levels of, 13 genes encoding MMPs, ADAMs, ADAMTSs and TIMPs (including MMP1, MMP9, ADAM9 and TIMP3) were found to be altered in drug-resistant sublines when compared with sensitive MCF-7. Conclusions Based on the expression analysis profiles, this report provides a preliminary insight into the rela- tionship between drug resistance and ECM components, which are related to invasion and metastasis. Correlation of each specific ECM component with drug resistance requires further analysis. Keywords Multidrug resistance Á cDNA microarray Á ECM Á Integrin Á MMP Á ADAM Introduction Multidrug resistance (MDR) describes a complex pheno- type whose predominant feature is resistance to wide range of structurally unrelated anticancer agents and is a serious limitation to the effective chemotherapeutic treatment [1]. There are several mechanisms by which cancer cells develop resistance to cytotoxic agents involving the alter- ations in various biochemical pathways. Mechanisms of drug resistance include decreased intracellular drug levels, which could result from increased drug efflux (ATP-bind- ing cassette transporters such as MDR1/P-glycoprotein), decreased conversion of drug to an active form, altered amount of target enzyme or receptor, decreased affinity of target enzyme or receptor for drug, enhanced repair of the drug-induced defect, decreased activity of an enzyme required for apoptosis, altered expression of genes for survival and altered target type [2]. Genome wide expres- sion analysis techniques may provide additional informa- tion on contribution of novel candidate genes to drug O ¨ . D. Is ¸eri Á M. D. Kars Á U. Gu ¨ndu ¨z (&) Department of Biological Sciences, Middle East Technical University, 06531 Ankara, Turkey e-mail: ufukg@metu.edu.tr O ¨ . D. Is ¸eri e-mail: odiseri@baskent.edu.tr F. Arpaci Department of Oncology, Gu ¨lhane Military School of Medicine, 06018 Ankara, Turkey 123 Cancer Chemother Pharmacol (2010) 65:447–455 DOI 10.1007/s00280-009-1048-z