Ability to acquire drug resistance arises early during the tumorigenesis process.

@article{citeulike:2808282, abstract = {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 pre-tumorigenic 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 pre-tumorigenic 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 pre-tumorigenic cells indicate that the drug efflux pump P-glycoprotein is responsible for the MDR phenotype in this pre-tumorigenic cell model.}, address = {Medical Research Council Clinical Sciences Centre, Imperial College Faculty of Medicine, Du Cane Road, Lonson, UK.}, author = {Yag\"{u}e, E. and Arance, A. and Kubitza, L. and O'Hare, M. and Jat, P. and Ogilvie, C. M. and Hart, I. R. and Higgins, C. F. and Raguz, S. }, citeulike-article-id = {2808282}, doi = {10.1158/0008-5472.CAN-06-2574}, issn = {0008-5472}, journal = {Cancer research}, keywords = {cancer, therapy}, month = {February}, number = {3}, pages = {1130--1137}, posted-at = {2008-05-17 21:52:29}, priority = {2}, title = {Ability to acquire drug resistance arises early during the tumorigenesis process.}, url = {http://dx.doi.org/10.1158/0008-5472.CAN-06-2574}, volume = {67}, year = {2007} }

TY - JOUR ID - citeulike:2808282 L3 - citeulike-article-id:2808282 TI - Ability to acquire drug resistance arises early during the tumorigenesis process. JF - Cancer research VL - 67 IS - 3 SP - 1130 EP - 1137 AD - Medical Research Council Clinical Sciences Centre, Imperial College Faculty of Medicine, Du Cane Road, Lonson, UK. SN - 0008-5472 N2 - 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 pre-tumorigenic 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 pre-tumorigenic 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 pre-tumorigenic cells indicate that the drug efflux pump P-glycoprotein is responsible for the MDR phenotype in this pre-tumorigenic cell model. KW - cancer KW - therapy AU - Yagüe, E AU - Arance, A AU - Kubitza, L AU - O'Hare, M AU - Jat, P AU - Ogilvie, CM AU - Hart, IR AU - Higgins, CF AU - Raguz, S PY - 2007/02/01/ UR - http://dx.doi.org/10.1158/0008-5472.CAN-06-2574 ER -