Regulation of the Sodium/Iodide Symporter in Breast

描述（由申请人提供）：钠/碘同运体（NIS）介导碘在甲状腺和哺乳期乳房中的转运。在一系列肿瘤模型中靶向表达表达nis的转基因促进了放射性碘治疗的成功，但这种方法受到成功实现基因转移到肿瘤中的要求的限制。促甲状腺激素（TSH）在甲状腺癌中激活内源性NIS是甲状腺癌有效成像和治疗的主要工具。MCF7乳腺癌细胞中NIS的基础表达通常较低，但维甲酸（RA）可显著刺激NIS的表达。类风湿关节炎治疗导致乳腺癌细胞和小鼠乳腺癌模型中放射性碘浓度显著升高。我们最近发现，RA对乳腺癌细胞系中NIS表达的刺激是视黄酸受体（RAR）异构体特异性的，主要由RAR（32）异构体介导，地塞米松增强了诱导作用。磷脂酰肌醇-3激酶（PIS激酶）信号转导途径的抑制剂完全阻断ra诱导的NIS mRNA和蛋白的表达。乳腺癌细胞中的信号转导途径与甲状腺癌中由TSH激活的刺激NIS表达的信号转导途径不同。我们的假设是，NIS在乳腺癌中的独特调节机制，不同于哺乳期乳腺或甲状腺，可以被定义和利用，以选择性地提供放射性碘，这将有效地诊断和治疗一些分化的乳腺癌。将调查以下具体目标：1. 确定ra刺激乳腺癌中磷脂酰肌醇-3 （PIS）激酶信号转导通路及NIS基因表达的下游介质的机制。我们将利用药物拮抗剂、激动剂、遗传学和功能蛋白质组学来绘制相关的相互作用因素。2. 通过最大化NIS蛋白表达、亚细胞定位和动力学，确定与甲状腺细胞相比，乳腺癌细胞系中优化NIS基因表达和功能碘摄取的机制和条件。3. 利用已确定的NIS基因和蛋白刺激因子的优化组合，在转基因和异种移植体内模型中最大限度地浓缩放射性碘并治疗肿瘤。这项研究的发现可能应用于放射性碘成像和乳腺癌的治疗，并进一步了解调节乳腺癌生长和分化的因素。

DESCRIPTION (provided by applicant): The sodium/iodide symporter (NIS) mediates iodide transport in the thyroid and lactating breast. Targeted expression of a NIS-expressing transgene in a range of tumor models has promoted successful radioiodine therapy, but this approach is limited by the requirement to successfully achieve gene transfer into the tumor. Activation of endogenous NIS in thyroid cancer by thyroid stimulating hormone (TSH) is the primary tool for effective imaging and treatment of thyroid cancer. Basal NIS expression in MCF7 breast cancer cells is generally low, but is markedly stimulated by retinoic acid (RA). RA treatment results in significant concentration of radioiodine in breast cancer cells and in mouse breast cancer models. We have recently shown that RA stimulation of NIS expression in breast cancer cell lines is retinoic acid receptor (RAR) isoform-specific, mediated predominantly by the RAR(32 isoform, and that dexamethasone enhances induction. Inhibitors of the phosphatidylinositol-3 kinase (PIS kinase) signal transduction pathway completely block RA-induced NIS mRNA and protein expression. The signal transduction pathways in breast cancer cells are distinct from those activated by TSH that stimulate NIS expression in thyroid cancer. Our hypothesis is that unique mechanisms of regulation of NIS in breast cancer, distinct from those in lactating breast or thyroid, can be defined and exploited to selectively deliver radioiodine that will be effective for diagnosis and treatment of some differentiated breast cancer. The following specific aims will be investigated; 1. Determine the mechanism of RA-stimulation of the phosphatidylinositol-3 (PIS) kinase signal transduction pathway and downstream mediators of NIS gene expression in breast cancer. We will utilize pharmacologic antagonists, agonists, genetics, and functional proteomics, to map the relevant interacting factors. 2. Define the mechanisms and conditions that optimize NIS gene expression and functional iodide uptake in breast cancer cell lines, compared to thyroid, through maximizing NIS protein expression, subcellular localization, and kinetics. 3. Utilize the defined optimized combinations of NIS gene and protein stimulatory factors in transgenic and xenograft in vivo models to maximally concentrate radioiodine and treat tumors. The findings from this study can potentially be applied to radioiodine imaging and treatment of breast cancer and further understanding the factors that regulate breast cancer growth and differentiation.