REGULATION OF THE SODIUM/IODIDE SYMPORTER IN BREAST

描述：（改编自申请人摘要）在哺乳期乳腺癌中 在乳腺中，碘在乳汁中的浓度是血浆的36倍 碘浓度，由于钠/碘同向转运体（NIS）的刺激。 一些依赖碘的乳腺癌也浓缩碘，高达7倍， 但乳腺癌的碘摄取必须增强， 治疗可能，类似于摄取所需的TSH刺激， 放射性碘导致甲状腺癌全反式维甲酸（RA）治疗 在MCF-7细胞中刺激碘摄取、MS mRNA和MS蛋白， 受体（ER）阳性人乳腺癌细胞系，在时间和剂量 依赖的方式。在ER阴性对照中未观察到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。体外克隆形成试验表明， RA刺激MCF-7细胞后的放射性碘。MCF-12 A细胞具有 丰富的MS蛋白，但没有功能性碘摄取。MS法规不同 与甲状腺相比，乳腺中的乳腺癌显著增加，并且与正常 乳腺和乳腺癌细胞系。我们建议研究规管 与正常乳腺相比，乳腺癌细胞系中的碘转运， 甲状腺细胞系，目标是优化碘吸收和选择性 靶向乳腺癌细胞。具体目标包括：1.确定 RA介导的NIS基因转录调控机制 利用选择性类视色素激动剂的乳房衍生细胞和具有 一系列内源性RAR和RXR表达。2.确定 NIS蛋白表达的特征，亚细胞定位， 与乳腺来源的NIS最大功能相关的动力学 细胞系和区分功能性碘摄取的那些特征， 表达NIS蛋白的细胞系。3.利用体外模型优化 RA刺激的乳腺癌细胞中的辐射介导的细胞杀伤。4. 开发体内模型，以确定 RA刺激的乳腺癌碘摄取，并确定 增强剂和辐射增敏剂。RA放射性碘摄取可能有助于 一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.