NIS Regulation in Breast Cancer

描述(由申请人提供)：这项研究提案的长期目标是开发一种新的方法来检测和治疗乳腺癌。Na+/I-转运蛋白(NIS)是一种跨膜糖蛋白，介导甲状腺滤泡上皮细胞摄取活性碘。选择性增加甲状腺组织中NIS的表达/功能是放射性碘治疗甲状腺癌有效的分子基础。由于NIS在哺乳期乳腺组织中高度表达，并且大多数人类乳腺肿瘤表达NIS，我们假设NIS在乳腺肿瘤中的表达/功能可以上调，从而实现靶向放射性核素成像和治疗。目的1.确定人绒毛膜促性腺激素(HCG)、反式维甲酸(Tra)和环氧合酶-2(COX-2)上调乳腺癌细胞NIS表达的机制；目的2.研究ras下游效应因子对乳腺癌细胞NIS表达的调控；以及目的3.建立临床前小鼠模型，高通量筛选选择性增加乳腺组织NIS表达/功能的因子(S)。这项拟议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(S)来增加乳腺肿瘤中NIS的表达和功能，使放射性核素能够定位和消融乳腺癌切除后残留的乳腺癌，从而防止疾病的复发和转移。

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.