REGULATION OF THE SODIUM/IODIDE SYMPORTER IN BREAST

描述：(改编自申请人的摘要)在哺乳期 与血浆相比，牛奶中的碘含量高达36倍 碘浓度，由于钠/碘同向转运体(NIS)的刺激。 一些激素依赖型乳腺癌也会浓缩碘，最高可达7倍， 但必须提高乳腺癌的碘摄取率，以制造放射性碘。 治疗可能，类似于摄取TSH所需的刺激 放射性碘进入甲状腺癌。全反式维甲酸(RA)治疗 刺激雌激素MCF-7细胞摄取碘、MS mRNA和MS蛋白 受体(ER)阳性的人乳腺癌细胞株的时间和剂量 依附时尚。ER阴性患者未见RA诱导的碘摄取 乳腺癌细胞系，MDA-MB 231，或正常乳腺来源的细胞系， MCF-12A。体外集落形成试验显示其选择性毒性 RA刺激MCF-7细胞后的放射性碘。MCF-12A细胞具有 丰富的MS蛋白质，但没有功能性的碘摄取。MS规则不同 乳房明显高于甲状腺，在正常情况下也不同 乳腺和乳腺癌细胞株。我们建议研究如何规范 乳腺癌细胞系中碘转运与正常乳腺和正常乳腺的比较 甲状腺细胞系，其目标是优化碘摄取并选择性地 靶向乳腺癌细胞。具体目标包括：1.确定 视黄酸介导的NIS基因转录调控机制 使用选择性维甲酸激动剂的乳房来源细胞和具有 一系列内源性RAR和RXR的表达。2.确定 NIS蛋白的表达、亚细胞定位和 乳房来源NIS最大功能相关的动力学研究 细胞系和那些区分功能性碘摄取的特征 表达NIS蛋白的细胞系。3.利用体外模型进行优化 RA刺激的辐射介导的乳腺癌细胞杀伤作用。4. 开发体内模型以确定其疗效和特异性 RA刺激乳腺癌摄取碘的实验研究 增强剂和辐射增敏剂。放射性碘摄取可能有助于 某些分化型乳腺癌的诊断和治疗。

DESCRIPTION: (Adapted from the applicant's abstract) In the lactating mammary gland, iodide is concentrated up to 36-fold in milk compared with the plasma iodide concentration, due to stimulation of the sodium/iodide symporter (NIS). Some hormone-dependent breast cancers also concentrate iodide, up to 7-fold, but iodide uptake in breast cancer must be enhanced to make radioiodine treatment possible, analagous to the TSH stimulation required for uptake of radioiodine into thyroid cancer. All-trans retinoic acid (RA) treatment stimulates iodide uptake, MS mRNA, and MS protein in MCF-7 cells, an estrogen receptor (ER) positive human breast cancer cell line, in a time and dose dependent fashion. No RA-induction of iodide uptake is seen in an ER-negative breast cancer cell line, MDA-MB 231, or a normal breast-derived cell line, MCF-12A. An in vitro clonogenic assay demonstrated selective toxicity of radioiodine following RA stimulation of MCF-7 cells. MCF-12A cells have abundant MS protein, but no functional iodide uptake. MS regulation differs significantly in the breast compared to the thyroid, and differs in normal breast and breast cancer cell lines. We propose to study the regulation of iodide transport in breast cancer cell lines compared to normal breast and thyroid cell lines, with the goals of optimzing iodide uptake and selectively targeting breast cancer cells. Specific aims include: 1. Determine the mechanism of RA-mediated transcriptional regulation of the NIS gene in breast-derived cells utilizing selective retinoid agonists and cell lines with a range of endogenous RAR and RXR expression. 2. To determine the characteristics of NIS protein expression, subcellular localization, and kinetics that are associated with maximal function of NIS in breast-derived cell lines and those features that distinguish functional iodide uptake among cell lines that express NIS protein. 3. Utilize an in vitro model to optimize RA-stimulated radiation-mediated cell killing in breast cancer cells. 4. Develop in vivo models to determine the efficacy and specificity of RA-stimulated iodide uptake into breast cancer and determine the influence of enhancers and radiation sensitizers. RA raioiodide uptake may be useful for diagnosis and treatment of some differentiated breast cancer.