Reduction of stimulated sodium iodide symporter expression by estrogen receptor ligands in breast cancer cells
Reduction of stimulated sodium iodide symporter expression by estrogen receptor ligands in breast cancer cells
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DOI：
10.1016/j.nucmedbio.2010.07.010
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发表时间：
2011-02-01
影响因子：
3.1
通讯作者：
Kim, Dong Wook
中科院分区：
文献类型：
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作者：
Cheong, Su-Jin;Jang, DooRye;Kim, Dong Wook
目的：钠碘同向转运体（NIS）介导泌乳期乳腺组织中的主动碘摄取，并且当其水平被全反式维甲酸（atRA）增强时，NIS已被提议作为乳腺癌的成像和放射治疗的靶点。重要的是，雌激素受体α（ER α）是乳腺癌细胞中atRA诱导的NIS基因表达的重要调节因子。在这项研究中，我们研究了雌激素受体激动剂的作用，（17 β-雌二醇，E-2）或拮抗剂[反式-羟基他莫昔芬（TOT）或雷洛昔芬（RAL）]治疗对ER α阳性乳腺癌（MCF-7）模型中NIS基因表达和碘摄取的调节。用体外I-125摄取试验测定NIS与E-2共孵育后的功能活性（10（-15）至10（-5）M）、TOT（5 × 10（-8）至5 × 10（-6）M）或RAL（5 × 10（-8）5 × 10（-6）M）。在相同的条件下，通过逆转录聚合酶链反应检测NIS mRNA的表达。结果：在细胞碘摄取实验中，单独给予E-2、TOT或RAL均不能促进肿瘤摄取I-125，而单独给予E-2、TOT或RAL均不能促进肿瘤摄取I-125。然而，当碘摄取刺激atRA，共处理与E-2。TOT或RAL以浓度依赖性方式降低I-125摄取。激素对MCF-7细胞NIS mRNA表达水平的影响相似。体内生物分布研究的结果表明，I-125摄取减少50%，在肿瘤组织中的小鼠用atRA/E-2治疗相比，仅用atRA.Conclusion肿瘤：我们的研究结果表明，atRA和ER配体的联合治疗可以限制由atRA诱导的NIS基因的功能活性，从而损害其作为诊断或放射治疗乳腺癌的目标。(C)2011 Elsevier Inc. All rights reserved.
Purpose: The sodium iodide symporter (NIS) mediates active iodide uptake in lactating breast tissue, and when its levels are enhanced by all-trans retinoic acid (atRA), NIS has been proposed as a target for the imaging and radiotherapy of breast cancer. Importantly, the estrogen receptor alpha (ER alpha) is an important regulator of atRA induced NIS gene expression in breast cancer cells. In this study, we investigated the effect of an ER agonist (17 beta-estradiol, E-2) or antagonist [trans-hydroxytamoxifen (TOT) or raloxifene (RAL)] treatment on the regulation of NIS gene expression and iodide uptake in an ER alpha-positive breast cancer (MCF-7) model.Methods: NIS functional activity was measured in vitro by I-125 uptake assay after incubation with E-2 (from 10(-15) to 10(-5) M), TOT (from 5x10(-8) to 5 x 10(-6) M), or RAL (from 5 x 10(-8) 5 x 10(-6) M) in the presence or absence of atRA (10(-7) M). Under the same conditions, NIS mRNA expression was examined by reverse transcriptase polymerase chain reaction. Athymic mice with MCF-7 xenograft tumors were treated with atRA alone or atRA together with E-2 to evaluate the change of I-125 uptake in tumor tissues in vivo.Results: In the iodide uptake study in cells, E-2, TOT, or RAL treatment alone did not stimulate I-125 uptake. However, when iodide uptake was stimulated by atRA, cotreatment with E-2. TOT or RAL decreased I-125 uptake in a concentration-dependent manner. The hormone effects on NIS mRNA expression levels in MCF-7 cells were similar. The results of the in vivo biodistribution study showed that I-125 uptake was reduced 50% in tumor tissues of mice treated with atRA/E-2 as compared to tumors treated only with atRA.Conclusion: Our results suggest that combination treatment of atRA and ER ligands could limit the functional activity of the NIS gene induced by atRA, thereby compromising its use as a target for diagnosis or radiotherapy in breast cancer. (C) 2011 Elsevier Inc. All rights reserved.