Abstract 954: ABCC/MRP multidrug transporters contribute to neuroblastoma biology, pathogenesis and clinical outcome, independently of any role in cytotoxic drug efflux

Abstract

Abstract We have previously shown that high levels of the multidrug transporters ABCC1/MRP1 (1,2) and ABCC4/MRP4 (3) are strongly predictive of poor outcome in the childhood cancer, neuroblastoma. Although the prognostic significance of ABCC1 may be explained in terms of cytotoxic drug resistance, none of the drugs used to treat children in these studies were ABCC4 substrates. This suggests that multidrug transporters can contribute to the malignant phenotype, independent of cytotoxic drug efflux, as we have recently outlined (4). To address this hypothesis, a MYCN-driven transgenic mouse neuroblastoma model was crossed with an Abcc1-deficient mouse strain or alternatively, treated with an ABCC1 inhibitor. Pharmacological inhibition or genetic depletion of ABCC1 significantly inhibited neuroblastoma development in MYCN transgenic mice, while knockdown of ABCC1 using siRNA reduced cell motility and clonogenicity in cultured neuroblastoma cells, and induced morphological differentiation. Analysis of a large neuroblastoma cohort of 209 primary untreated tumors revealed that amongst the 12 members of the ABCC gene family, expression of only ABCC1, ABCC4 and also ABCC3 were predictive of neuroblastoma outcome. We confirmed a highly significant association between high levels of either ABCC1 or ABCC4 and poor outcome (p<0.0001), but in addition, found the surprising result of a highly significant association between low expression of ABCC3 and poor outcome (p<0.0001). Expression levels of ABCC1, ABCC3 and ABCC4 were all independently prognostic of outcome and their combined expression pattern defined a subgroup of patients with a survival rate of less than 20%. These results were confirmed by analysis of a large publicly available neuroblastoma gene expression database. siRNA knockdown of ABCC4, or over-expression of ABCC3, also influenced multiple biological characteristics of neuroblastoma cells, resulting in reduced proliferation and migration, and enhanced morphological differentiation. This study provides the first evidence that ABCC multidrug transporters can contribute to neuroblastoma biology and pathogenesis independently of any role in chemotherapeutic drug efflux, and suggests that ABCC1, ABCC3 and ABCC4 represent attractive targets for therapeutic intervention. 1) New Engl J Med 334:231-238, 1996 2) J Clin Oncol 24:1546-53, 2006 3) Mol Cancer Ther 4:547-53, 2005 4) Nat Rev Cancer, 10:147-156, 2010 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 954. doi:10.1158/1538-7445.AM2011-954