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Ability to Acquire Drug Resistance Arises Early during the Tumorigenesis Process

¹ Medical Research Council Clinical Sciences Centre, Imperial College Faculty of Medicine; ² Ludwig Institute for Cancer Research-University College London, Breast Cancer Laboratory, Department of Surgery, Royal Free and University College London Medical School; ³ Department of Neurodegenerative Disease, Institute of Neurology, University College London; ⁴ Cytogenetics Department, Guy's and St. Thomas' Hospital Trust; and ⁵ Centre for Tumour Biology, Institute of Cancer and Cancer Research UK Clinical Centre, Bart's and The London Queen Mary School of Medicine and Dentistry, London, United Kingdom

Requests for reprints: Selina Raguz, Membrane Transport Biology, Medical Research Council Clinical Sciences Centre, Imperial College Faculty of Medicine, Du Cane Road, London W12 0NN, United Kingdom. Phone: 44-20-8383-8269; Fax: 44-20-8383-8337; E-mail: s.raguz{at}csc.mrc.ac.uk.

Resistance to chemotherapy is one of the principal causes of cancer mortality and is generally considered a late event in tumor progression. Although cellular models of drug resistance have been useful in identifying the molecules responsible for conferring drug resistance, most of these cellular models are derived from cell lines isolated from patients at a late stage in cancer progression. To ask at which stage in the tumorigenic progression does the cell gain the ability to acquire drug resistance, we generated a series of pretumorigenic and tumorigenic cells from human embryonic skin fibroblasts by introducing, sequentially, the catalytic subunit of telomerase, SV40 large T and small T oncoproteins, and an oncogenic form of ras. We show that the ability to acquire multidrug resistance (MDR) can arise before the malignant transformation stage. The minimal set of changes necessary to obtain pretumorigenic drug-resistant cells is expression of telomerase and inactivation of p53 and pRb. Thus, the pathways inactivated during tumorigenesis also confer the ability to acquire drug resistance. Microarray and functional studies of drug-resistant pretumorigenic cells indicate that the drug efflux pump P-glycoprotein is responsible for the MDR phenotype in this pretumorigenic cell model. [Cancer Res 2007;67(3):1130–7]

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