Expression of multidrug transporter MRP4/ABCC4 is a marker of poor prognosis in neuroblastoma and confers resistance to irinotecan in vitro

Abstract

Members of the multidrug resistance -associated protein (MRP) family of transporters are believed to contribute to cytotoxic drug resistance and chemotherapy failure. We observed frequent MRP4 overexpression in aggressive primary neuroblastoma, a disease for which we have previously shown MRP1 to be a prognostic indicator. High MRP4 expression correlated with MYCN oncogene amplification and was significantly associated with poor clinical outcome. Although MRP4 is known to transport some nucleoside analogues, it has not previously been associated with resistance to drugs used to treat solid tumors. We now show that it mediates substantial resistance in vitro to the topoisomerase I poison irinotecan/CPT-11 and its active metabolite SN-38. These results suggest that MRP4 will be a useful prognostic marker for neuroblastoma and that clinical trials of irinotecan as a neuroblastoma treatment should monitor MRP4 expression. The same may be true for other tumor types expressing high levels of the transporter. [Mol Cancer Ther 2005;4(4):547 -53]

Introducing, OncoTarget

“…High levels of this gene are strongly predictive of poor outcome in cancers, including neuroblastoma, colorectal cancer and esophageal squamous cell carcinoma [18,40,41]. In addition, MRP4 has been shown to have remarkable ability to modulate cellular signaling processes besides its versatile efflux transport function as a potential therapeutic target in cancer treatment [17,42].…”

The Role of Multi-Drug Resistance Associated Protein 4 and P-glycoprotein in Resistance of Neuroblastoma to Topotecan and Irinotecan

“…When compared to methods such as RT-PCR to detect mRNA expression (10,11,12,110) Norris and colleagues demonstrated MRP4 mRNA expression in 100% of 52 neuroblastomas from untreated patients (110). In this population of 52 patients, high MRP4 mRNA expression was a significant indicator of poor survival.…”

“…ABC transporters also confer resistance to other cytotoxic drugs traditionally used in high-risk neuroblastoma therapy (i.e., doxorubicin, etoposide, and vincristine). Furthermore, MRP1, Pgp, and MRP4 are expressed in neuroblastoma, and high levels of mRNA expression of these transporters is predictive of poor overall survival and event-free survival (10,11,12,110). However, the relation between expression of ABC transport proteins in neuroblastoma cells and antitumor response to ABC transporter substrates has not been evaluated.…”

“…Norris and colleagues reported that MRP4 mRNA expression was correlated with MYCN amplification in neuroblastoma and was an independent predictor of poor outcome (110). Although MYCN has not yet been shown to activate MRP4 transcription, the MRP4 promoter contains an E box.…”

“…In one study of the mRNA expression of ABC transporters in neuroblastoma, BCRP mRNA was detected in neuroblastoma tumor specimens from patients, but the level of mRNA expression was not related to treatment outcome (110). The only other study of BCRP expression in neuroblastoma used immunohistochemistry to demonstrate BCRP protein expression in the xenograft NB1691 (130).…”