1. ¹Memorial Sloan-Kettering Cancer Center, New York, New York
2. ²Albert Einstein College of Medicine, New York, New York
3. ³Instituti Ortopedici Rizzoli, Bologna, Italy

Correspondence: Dr. Marta Sanchez-Carbayo, Division of Molecular Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021. E-mail: cordon-c@mskcc.org

Received 26 September 2002.

Abstract

The expression patterns of the osteosarcoma cell line U-2 OS, and three derived subclones containing stably transfected MDR1, NEO and MDR1/NEO genes were compared using cDNA microarrays comprising 8976 known genes and expressed sequenced tags. Data provided new insights into three critical issues. First, MDR1 overexpression was associated with altered expression of genes related to several cellular pathways, including (a) drug influx/efflux (eg, dynamin 3), (b) metabolic enzymes (eg, monoamine oxidase A), (c) cell adhesion (eg, EPCAM), (d) apoptotic signaling (eg, I-TRAF), (e) senescence (eg, telomerase RNA binding protein staufen), (f) tumor suppression-related genes (eg, KISS-1 and ephrin B3), and (g) immune system receptors (eg, LENG2). MDR1, EPCAM, and ephrin B3 expression was confirmed by immunohistochemistry. Second, MDR1 transfected cells selected with either doxorubicin or neomycin showed distinct expression profiles that could be related to differential selection. Moreover, hierarchical clustering indicated that cells transfected with MDR1 alone, or cotransfected with NEO, displayed more closely related expression profiles than cells transfected only with NEO. Third, transfection with NEO and selection with neomycin produced a considerable number of expression changes within the cell. This study further elucidates the genetic events associated with MDR1 expression and identifies novel targets associated with multidrug resistance.