Elevated multidrug resistance-associated protein 4 (MRP4) expression in localized prostate cancer—A potential androgen regulated protein

Abstract

20022 Background: MRP4 is an ATP-binding cassette transporter and amphipathic anion efflux pump which transports prostaglandins, nucleoside analogues, glutamate and phosphate analogues. High MRP4 expression is prognostic of poor outcome in neuroblastoma and also correlates with MYCN amplification, suggesting regulation by this oncogene. Although MRP4 is known to be expressed in normal prostate epithelium, its expression in prostate cancer (PC) is undefined. This study aimed to define the pattern of expression of MRP4 in normal and malignant prostate tissue and assess the association with androgen exposure. Methods: 84 radical prostatectomy specimens from patients with clinically localized PC (22 neoadjuvant androgen ablation therapy, 62 no neoadjuvant treatment), 42 specimens of hyperplasia adjacent to PC and 16 cases of advanced PC were assessed for MRP4 expression using in situ hybridisation and immunohistochemistry. PC cell lines were assessed by immunoblotting. Results: There were significantly higher levels of MRP4 mRNA and protein expression in localized PC compared to hyperplasia (p=0.006). Conversely, MRP4 protein levels were significantly decreased in PCs treated with neoadjuvant androgen ablation therapy compared to cancers exposed to normal testosterone levels (p < 0.0001). There was also a trend towards decreased MRP4 expression in advanced PCs. Furthermore, immunoblotting revealed that MRP4 protein was more highly expressed in androgen-dependent (LNCaP) compared to androgen-independent (PC3/DU145) cell lines. In addition, in a panel of 14 normal human tissues only kidney and prostate tissue expressed MRP4 protein suggesting limited expression of MRP4 in human tissues. Discussion: Elevated MRP4 expression is found in malignant compared to benign prostate tissue while lower MRP4 expression is seen after androgen ablation suggesting that MRP4 may be an androgen-regulated gene. In addition, there is relatively little expression of MRP4 in normal tissues. These data suggest that MRP4 is important in the progression to PC and that it may be a potential therapeutic target. No significant financial relationships to disclose.