The mammary gland sodium/iodide symporter (mgNIS)

描述(申请人提供)：钠转运体(NIS)是一种质膜蛋白，在甲状腺和其他组织，包括唾液腺、胃粘膜和哺乳期乳腺(MG)中介导主动的I-转运。NIS在每个组织中受到不同的调控。NIS介导的甲状腺I-转运是甲状腺激素生物合成的第一步。NIS在甲状腺癌中的内源性功能表达是目前唯一有效且无副作用的抗癌靶向放射治疗的基础，即放射性碘治疗，该疗法已成功应用于甲状腺癌60多年。本课题组分离了NIS编码基因，并制备了抗NIS抗体。我们已经确定了甲状腺NIS及其调节的特征。乳腺NIS(MgNIS)介导乳汁细胞主动的I-转运，I-通过不同的转运体被动地转运到乳汁中。MgNIS在哺乳期MG中表达，但在非哺乳期MG中不表达。MgNIS受雌激素、催乳素和催产素的调节。转基因小鼠的乳腺癌表现出mgNIS介导的主动I摄取。仅有的两种内源性功能性NIS表达的癌症是甲状腺癌和乳腺癌。超过80%的人类乳腺癌表达mgNIS，但目前尚不清楚这些NIS中有多少是功能性的。正常的非哺乳期人类乳房样本不表达mgNIS。与其他癌症相比，NIS在乳腺癌中的内源性表达提供了巨大的优势，其中一些癌症中的NIS已通过病毒介导的基因转移异位表达。为了确定mgNIS在乳腺细胞中的特征，并确定其在乳腺癌诊断和治疗中的潜在价值，我们建议：1)表征mgNIS在乳腺细胞系中的调节；b)研究全身和局部调节因素对mgNIS在体内表达的影响；c)确定低温和化学伴侣是否促进mgNIS靶向质膜；d)通过评估可能的顶端I-转运体的作用来补充我们对乳腺I-转位的理解。2)建立放射性碘治疗方案，评价其对动物模型腺癌的治疗效果。3)探讨mgNIS在人乳腺原发肿瘤和转移瘤细针抽吸物中的功能表达及其与乳腺癌其他参数的关系。

DESCRIPTION (provided by applicant): The Na symporter (NIS) is a plasma membrane protein that mediates active I- transport in the thyroid and other tissues, including salivary glands, gastric mucosa, and lactating mammary glands (MG). NIS is regulated differently in each tissue. NIS-mediated I- transport in the thyroid is the first step in thyroid hormone biosynthesis. Endogenous functional expression of NIS in thyroid cancer is the foundation for the single most effective and most side effect-free anti-cancerous targeted radiation therapy available, i.e. radioiodide therapy, which has been successfully used in thyroid cancer for over 60 years. Our group isolated the cDNA encoding NIS and generated anti-NIS Abs. We have characterized thyroid NIS and its regulation. Mammary gland NIS (mgNIS) mediates active I- transport in lactating mammary cells, from which I- is passively translocated via a different transporter to the milk. mgNIS is expressed in lactating (but not in non-lactating) MG. mgNIS is regulated by estrogen, prolactin, and oxytocin. Mammary adenocarcinomas in transgenic mice display mgNIS-mediated active I- uptake. The only two cancers in which endogenous functional NIS is expressed are thyroid cancer and breast cancer. Over 80% of human breast cancers express mgNIS, but it is still unknown in what percentage of these NIS is functional. Normal non-lactating human breast samples do not express mgNIS. The endogenous expression of NIS in breast cancer provides an immense advantage over other cancers, into some of which NIS has been ectopically expressed by virus-mediated gene transfer. To characterize mgNIS in mammary cells and ascertain its potential value in breast cancer diagnosis and treatment, we propose: 1. a) To characterize the regulation of mgNIS in mammary cell lines; b) to investigate the effects of systemic and local regulatory factors on the expression of mgNIS in vivo; c) to determine whether low temperature and chemical chaperones promote targeting of mgNIS to the plasma membrane; d) to complement our understanding of I- translocation in the lactating mammary gland by assessing the role of putative apical I- transporters. 2) To develop a radioiodide therapeutic protocol and assess its effectiveness in the treatment of adenocarcinomas in animal models. 3) To ascertain, in fine needle aspirates from both human primary breast tumors and metastases, the functional expression of mgNIS and its possible correlation with other breast cancer parameters.