NIS Regulation in Breast Cancer

描述（由申请人提供）：本研究提案的长期目标是开发一种检测和治疗乳腺癌的新方法。 Na+/I-同向转运体（NIS）是介导甲状腺滤泡上皮细胞主动碘摄取的跨膜糖蛋白。 甲状腺组织中选择性增加NIS表达/功能是甲状腺癌患者有效放射性碘治疗的分子基础。 由于NIS在哺乳期乳腺组织中高度表达，并且大多数人乳腺肿瘤表达NIS，因此我们假设NIS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。 提出了三个具体目标来鉴定将选择性地增加乳腺肿瘤中NIS表达的因素：目的2.探讨人绒毛膜促性腺激素（hCG）、反式维甲酸（tRA）和环氧合酶-2（考克斯-2）上调人乳腺癌细胞NIS表达的机制。研究人乳腺癌细胞中ras下游效应子对NIS的调控;目的3.建立临床前小鼠模型，以高通量筛选将选择性增加乳腺组织中NIS表达/功能的因子。 所提出的研究的成功将使我们更接近于使用所鉴定的化合物进行人体临床试验，以增加乳腺肿瘤中的NIS表达和功能，使得放射性核素能够定位和消融乳房切除术后的残留乳腺癌，从而可以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.