Meyer zu Schwabedissen Henriette E, Tirona Rommel G, Yip Cindy S, Ho Richard H, Kim Richard B
Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, Canada.
Cancer Res. 2008 Nov 15;68(22):9338-47. doi: 10.1158/0008-5472.CAN-08-0265.
The ligand-activated nuclear receptor pregnane X receptor (PXR) is known to play a role in the regulated expression of drug metabolizing enzymes and transporters. Recent studies suggest a potential clinically relevant role of PXR in breast cancer. However, the relevant pathway or target genes of PXR in breast cancer biology and progression have not yet been fully clarified. In this study, we show that mRNA expression of organic anion transporter polypeptide 1A2 (OATP1A2), a transporter capable of mediating the cellular uptake of estrogen metabolites, is nearly 10-fold greater in breast cancer compared with adjacent healthy breast tissues. Immunohistochemistry revealed exclusive expression of OATP1A2 in breast cancer tissue. Interestingly, treatment of breast cancer cells in vitro with the PXR agonist rifampin induced OATP1A2 expression in a time-dependent and concentration-dependent manner. Consistent with its role as a hormone uptake transporter, induction of OATP1A2 was associated with increased uptake of estrone 3-sulfate. The rifampin response was abrogated after small interfering RNA targeting of PXR. We then identified a PXR response element in the human OATP1A2 promoter, located approximately 5.7 kb upstream of the transcription initiation site. The specificity of PXR-OATP1A2 promoter interaction was confirmed using chromatin immunoprecipitation. Importantly, we used a novel potent and specific antagonist of PXR (A-792611) to show the reversal of the rifampin effect on the cellular uptake of E(1)S. These data provide important new insights into the interplay between a xenobiotic nuclear receptor PXR and OATP1A2 that could contribute to the pathogenesis of breast cancer and may also prove to be heretofore unrecognized targets for breast cancer treatment.
配体激活的核受体孕烷X受体（PXR）在药物代谢酶和转运蛋白的调控表达中发挥作用。最近的研究表明PXR在乳腺癌中可能具有临床相关作用。然而，PXR在乳腺癌生物学和进展中的相关途径或靶基因尚未完全阐明。在本研究中，我们发现有机阴离子转运多肽1A2（OATP1A2）的mRNA表达在乳腺癌中比相邻的健康乳腺组织高近10倍，OATP1A2是一种能够介导雌激素代谢物细胞摄取的转运蛋白。免疫组织化学显示OATP1A2在乳腺癌组织中特异性表达。有趣的是，用PXR激动剂利福平体外处理乳腺癌细胞以时间和浓度依赖性方式诱导OATP1A2表达。与其作为激素摄取转运蛋白的作用一致，OATP1A2的诱导与硫酸雌酮摄取增加相关。靶向PXR的小干扰RNA后，利福平反应被消除。然后我们在人OATP1A2启动子中鉴定出一个PXR反应元件，位于转录起始位点上游约5.7 kb处。使用染色质免疫沉淀证实了PXR - OATP1A2启动子相互作用的特异性。重要的是，我们使用一种新型强效且特异性的PXR拮抗剂（A - 792611）来显示利福平对E(1)S细胞摄取作用的逆转。这些数据为异生物质核受体PXR和OATP1A2之间的相互作用提供了重要的新见解，这可能有助于乳腺癌的发病机制，也可能被证明是迄今为止未被认识的乳腺癌治疗靶点。
