NIS Regulation in Breast Cancer

描述（由申请人提供）：本研究计划的长期目标是开发一种检测和治疗乳腺癌的新方法。Na+/I-同调体（NIS）是一种跨膜糖蛋白，在甲状腺滤泡上皮细胞中介导碘的活性摄取。选择性地增加甲状腺组织中NIS的表达/功能是放射性碘治疗甲状腺癌患者有效的分子基础。由于NIS在哺乳期乳腺组织中高度表达，而且大多数人类乳腺肿瘤都表达NIS，我们假设NIS的表达/功能可以在乳腺肿瘤中上调，从而实现靶向放射性核素成像和治疗。我们提出了三个特定的目的来确定在乳腺肿瘤中选择性增加NIS表达的因子：目的1。确定人绒毛膜促性腺激素（hCG）、反式维甲酸（tRA）、环氧化酶-2 （Cox-2）在人乳腺癌细胞中上调NIS的机制；目标2。ras下游效应物对人乳腺癌细胞NIS调控的研究和Aim 3。建立临床前小鼠模型，对乳腺组织中选择性增加NIS表达/功能的因子进行高通量筛选。这项研究的成功将使我们更接近于进行人体临床试验，使用已确定的化合物来增加乳腺肿瘤中的NIS表达和功能，使放射性核素能够定位和消融乳房切除术后残留的乳腺癌，从而预防疾病的复发和转移。

DESCRIPTION (provided by applicant): The long-term objective of this research proposal is to develop a novel approach to detect and to treat breast cancer. Na+/I- symporter (NIS) is a transmembrane glycoprotein that mediates active iodide uptake in thyroid follicular epithelial cells. Selectively increased NIS expression/function in thyroid tissue is the molecular basis of effective radioiodine treatment for patients with thyroid cancers. Since NIS is highly expressed in lactating breast tissues and the majority of human breast tumors express NIS, we hypothesize that NIS expression/function can be up-regulated in breast tumors enabling targeted radionuclide imaging and therapy. Three specific aims are proposed to identify the factor(s) that will selectively increase NIS expression in breast tumors: Aim 1. Determine the mechanism of NIS up-regulation by human chorionic gonadotropin (hCG), trans-retinoic acid (tRA), and cyclooxygenase-2 (Cox-2) in human breast cancer cells; Aim 2. Investigate NIS regulation by downstream effectors of ras in human breast cancer cells; and Aim 3. Establish pre-clinical mouse models to perform high throughput screening for the factor(s) that will selectively increase NIS expression/function in breast tissues. The success of the proposed study will take us one step closer to proceed to human clinical trials using identified compound(s) to increase NIS expression and function in breast tumors enabling radionuclide to localize and ablate residual breast cancer following mastectomy, such that recurrence and metastasis of the disease can be prevented.