Willhauck Michael J, Sharif-Samani Bibi, Senekowitsch-Schmidtke Reingard, Wunderlich Nathalie, Göke Burkhard, Morris John C, Spitzweg Christine
Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany.
Breast Cancer Res Treat. 2008 May;109(2):263-72. doi: 10.1007/s10549-007-9646-0. Epub 2007 Jul 18.
The sodium iodide symporter (NIS) mediates iodide uptake in the thyroid gland as well as in lactating breast, and is also expressed in the majority of breast cancers. Recently, we have reported stimulation of all-trans retinoic acid (atRA)-induced NIS expression in the human breast cancer cell line MCF-7 by dexamethasone (Dex), resulting in an enhanced therapeutic effect of (131)I in vitro.
In the current study we examined the efficacy of Dex stimulation of atRA-induced NIS expression in vivo in MCF-7 xenotransplants in nude mice.
After systemic treatment with atRA alone or in combination with Dex, iodide accumulation in the tumors was assessed by gamma camera imaging and gamma counter analysis. In addition, NIS expression was examined on RNA and protein level by RT-PCR and immunohistochemistry, respectively.
Using gamma camera imaging after intraperitoneal injection of 18.5 MBq (123)I, no iodide accumulation was detected in tumors of untreated mice or mice treated with atRA only. After combined treatment with atRA/Dex significant (123)I accumulation was detected in MCF-7 xenografts, which, by ex vivo gamma counting revealed a 3.3-fold increase in iodide accumulation as compared to control tumors. Surprisingly, in a subset of mice treated with atRA or atRA/Dex iodide accumulation was also detected in the normal mammary glands. In a normal human mammary epithelial cell line HB-2, however, no functional NIS expression was induced after treatment with atRA and/or Dex in vitro. Further, NIS mRNA and protein expression was detected in atRA/Dex treated MCF-7 tumors by RT-PCR and immunohistochemistry, respectively.
Treatment with Dex in the presence of atRA is able to induce significant amounts of iodide accumulation in breast cancer xenotransplants in vivo due to stimulation of functional NIS protein expression, which opens exciting perspectives for a possible diagnostic and therapeutic role of radioiodine in the treatment of breast cancer.
碘化钠同向转运体（NIS）介导甲状腺以及哺乳期乳腺对碘化物的摄取，并且在大多数乳腺癌中也有表达。最近，我们报道了地塞米松（Dex）可刺激全反式维甲酸（atRA）诱导人乳腺癌细胞系MCF-7中NIS的表达，从而在体外增强了（131）I的治疗效果。
在本研究中，我们检测了Dex刺激atRA诱导的NIS在裸鼠MCF-7异种移植瘤体内表达的效果。
在单独使用atRA或与Dex联合进行全身治疗后，通过γ相机成像和γ计数器分析评估肿瘤中碘化物的蓄积情况。此外，分别通过逆转录聚合酶链反应（RT-PCR）和免疫组织化学在RNA和蛋白质水平检测NIS的表达。
腹腔注射18.5 MBq（123）I后利用γ相机成像，未治疗的小鼠或仅用atRA治疗的小鼠肿瘤中未检测到碘化物蓄积。atRA与Dex联合治疗后，在MCF-7异种移植瘤中检测到显著的（123）I蓄积，通过离体γ计数显示，与对照肿瘤相比，碘化物蓄积增加了3.3倍。令人惊讶的是，在一部分用atRA或atRA/Dex治疗的小鼠的正常乳腺中也检测到碘化物蓄积。然而，在正常人乳腺上皮细胞系HB-2中，体外经atRA和/或Dex处理后未诱导功能性NIS表达。此外，分别通过RT-PCR和免疫组织化学在atRA/Dex处理的MCF-7肿瘤中检测到NIS mRNA和蛋白质表达。
在atRA存在的情况下用Dex治疗能够在体内乳腺癌异种移植瘤中诱导大量碘化物蓄积，这是由于功能性NIS蛋白表达受到刺激，这为放射性碘在乳腺癌治疗中可能的诊断和治疗作用开辟了令人兴奋的前景。
