EXPRESSION OF THE MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN (MRP) GENE CORRELATES WITH AMPLIFICATION AND OVEREXPRESSION OF THE N-MYC ONCOGENEIN CHILDHOOD NEUROBLASTOMA

The MRP gene (Cole et at, Science (Washington DC), 258: 1650-1654, 199 2) encodes a membrane-bound glycoprotein the expression of which corre lates with non-P-glycoprotein-mediated multidrug resistance in a varie ty of cultured human cell lines. Using an RNA-polymerase chain reactio n assay, expression of this gene was examined in the highly chemoresis tant pediatric malignancy, neuroblastoma. MRP expression was observed in 5 human neuroblastoma cell lines and in all 25 primary neuroblastom a tumors of stage I through IVS. Tumors with amplification of the N-my c oncogene were found to have significantly higher MRP expression than those with no amplification (P = 0.0016). Expression of the MRP gene in the tumor specimens was highly correlated with expression of the N- myc gene (P = 0.0009), while expression of the MDR1 gene, encoding P-g lycoprotein, was not related to expression of either the N-myc or MRP genes. Decreased expression of the N-myc oncogene in neuroblastoma cel l lines SH-SY5Y and BE(2)-C, following treatment with retinoic acid, w as paralleled by down-regulation of MRP gene expression, contrasting w ith increased expression of the MDR1 gene. Expression of the MRP gene is thus common in both primary neuroblastoma tumors and cultured cell lines, and correlates with amplification and overexpression of the N-m yc oncogene, which is central to the malignant phenotype of this disea se.