The mammary gland sodium/iodide symporter (mgNIS)

乳腺钠/碘同向转运体 (mgNIS)

• 批准号: 6679737
• 负责人: Nancy Carrasco
• 金额: $ 35.96万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6679737
• 关键词: MCF7 cell; SDS polyacrylamide gel electrophoresis; adenocarcinoma; breast neoplasms; cell membrane; fine needle aspiration; flow cytometry; human tissue; immunofluorescence technique; immunoprecipitation; iodine; ion transport; laboratory mouse; lactation; magnetic resonance imaging; mammary gland; membrane transport proteins; metastasis; molecular chaperones; neoplasm /cancer diagnosis; neoplasm /cancer therapy; phosphorylation; polymerase chain reaction; protein transport; sodium ion; western blottings

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.

描述（由申请人提供）：Na symporter （NIS）是一种质膜蛋白，介导甲状腺和其他组织（包括唾液腺、胃粘膜和泌乳乳腺（MG））中的活性I-运输。NIS在每个组织中受到不同的调节。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最有效、最无副作用的单一抗癌靶向放射治疗的基础，即放射性碘化物治疗，已成功用于甲状腺癌超过60年。我们小组分离了编码NIS的cDNA并生成了抗NIS抗体。我们对甲状腺NIS及其调控进行了表征。乳腺NIS （mgNIS）介导泌乳乳腺细胞中I-的主动转运，其中I-通过不同的转运体被动转运到乳汁中。mgNIS在泌乳MG中表达（而在非泌乳MG中不表达）。mgNIS受雌激素、催乳素和催产素调节。转基因小鼠乳腺腺癌显示mgnis介导的I-摄取活性。仅有的两种表达内源性功能性NIS的癌症是甲状腺癌和乳腺癌。超过80%的人类乳腺癌表达mgNIS，但仍不清楚这些NIS中有多少是功能性的。正常的非哺乳期人类乳腺样本不表达mgNIS。与其他癌症相比，NIS在乳腺癌中的内源性表达具有巨大的优势，其中一些癌症通过病毒介导的基因转移异位表达NIS。为了确定乳腺细胞中mgNIS的特征并确定其在乳腺癌诊断和治疗中的潜在价值，我们提出：1。a)表征乳腺细胞系中mgNIS的调控；b)研究体内系统和局部调控因子对mgNIS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)通过评估假定的顶端I-转运体的作用来补充我们对泌乳乳腺中I-易位的理解。2)制定放射性碘治疗方案，并在动物模型上评估其治疗腺癌的有效性。3)在人原发性乳腺肿瘤和转移性乳腺肿瘤的细针抽吸液中，确定mgNIS的功能表达及其与其他乳腺癌参数的可能相关性。