Regulation of the Sodium/Iodide Symporter in Breast

描述(申请人提供)：钠/碘同向转运体(NIS)介导碘在甲状腺和哺乳期乳房的转运。在一系列肿瘤模型中靶向表达NIS的转基因已经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)激活甲状腺癌内源性NIS是甲状腺癌有效成像和治疗的主要工具。MCF7乳腺癌细胞的基础NIS表达普遍较低，但受维甲酸(RA)明显刺激。RA治疗导致乳腺癌细胞和小鼠乳腺癌模型中放射性碘的显著浓度。我们最近发现，RA刺激乳腺癌细胞株NIS的表达是视黄酸受体(RAR)亚型特异性的，主要由RAR(32)亚型介导，地塞米松可以增强诱导作用。磷脂酰肌醇-3激酶(PIS)信号转导通路的抑制剂完全阻断RA诱导的NIS基因和蛋白的表达。乳腺癌细胞中的信号转导途径与TSH激活的刺激甲状腺癌中NIS表达的信号转导途径不同。我们的假设是，乳腺癌中NIS调节的独特机制，不同于乳汁或甲状腺中的机制，可以被定义并利用来选择性地传递放射性碘，这将对某些分化型乳腺癌的诊断和治疗有效。研究的具体目标如下：1.确定RA刺激乳腺癌中磷脂酰肌醇-3(PiS)信号转导通路的机制及NIS基因表达的下游介体。我们将利用药理拮抗剂、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图。2.确定通过最大化NIS蛋白表达、亚细胞定位和动力学，优化NIS基因表达和功能性碘摄取的机制和条件。3.在转基因和异种移植体内模型中，利用已确定的NIS基因和蛋白质刺激因子的优化组合，最大限度地浓缩放射性碘，治疗肿瘤。这项研究的发现可能应用于乳腺癌的放射性碘成像和治疗，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.