Interplay between the nuclear receptor pregnane X receptor and the uptake transporter organic anion transporter polypeptide 1A2 selectively enhances estrogen effects in breast cancer.
Interplay between the nuclear receptor pregnane X receptor and the uptake transporter organic anion transporter polypeptide 1A2 selectively enhances estrogen effects in breast cancer.
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DOI：
10.1158/0008-5472.can-08-0265
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发表时间：
2008-11-15
期刊：
影响因子：
11.2
通讯作者：
Kim RB
中科院分区：
文献类型：
--
作者：
Meyer zu Schwabedissen HE;Tirona RG;Yip CS;Ho RH;Kim RB
已知配体激活的核受体PXR在药物代谢酶和转运蛋白的调节表达中起作用。最近的研究表明PXR在乳腺癌中具有潜在的临床相关作用。然而，PXR在乳腺癌生物学和进展中的相关通路或靶基因尚未完全阐明。在这项研究中，我们发现，乳腺癌中OATP 1A 2（一种能够介导雌激素代谢物细胞摄取的转运蛋白）的mRNA表达比邻近的健康乳腺组织高近10倍。免疫组化结果显示OATP 1A 2在乳腺癌组织中特异性表达。有趣的是，在体外用PXR激动剂利福平处理乳腺癌细胞以时间和浓度依赖性方式诱导OATP 1A 2表达。与作为激素摄取转运蛋白的作用一致，OATP 1A 2的诱导与雌酮3-硫酸盐的摄取增加相关。利福平反应在PXR的si-RNA靶向后被消除。然后，我们确定了一个PXR反应元件在人OATP 1A 2启动子，位于转录起始位点上游约5.7 kb。使用染色质免疫沉淀法证实了PXR-OATP 1A 2启动子相互作用的特异性。重要的是，我们使用了一种新的有效和特异性的PXR拮抗剂（A-792611）来证明利福平对E1 S细胞摄取的逆转作用。这些数据提供了重要的新的见解之间的相互作用的异生核受体PXR和OATP 1A 2，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的目标。
The ligand-activated nuclear 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 OATP1A2, a transporter capable of mediating the cellular uptake of estrogen metabolites, is nearly 10-fold greater in breast cancer compared to 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- and concentration-dependent manner. Consistent with a role as a hormone uptake transporter, induction of OATP1A2 was associated with increased uptake of estrone 3-sulfate. The rifampin response was abrogated after si-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 utilized a novel potent and specific antagonist of PXR (A-792611) to demonstrate the reversal of the rifampin effect on the cellular uptake of E1S. 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.