The mammary gland sodium/iodide symporter (mgNIS)

乳腺钠/碘同向转运体 (mgNIS)

• 批准号: 7115479
• 负责人: Nancy Carrasco
• 金额: $ 5.9万
• 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 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7115479
• 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 协同转运蛋白（NIS）是一种质膜蛋白，介导甲状腺和其他组织（包括唾液腺、胃粘膜和哺乳期乳腺（MG））中的主动 I-转运。 NIS 在每个组织中受到不同的调节。 NIS 介导的 I- 甲状腺转运是甲状腺激素生物合成的第一步。甲状腺癌中 NIS 的内源性功能表达是现有单一最有效、最无副作用的抗癌靶向放射治疗（即放射性碘治疗）的基础，该治疗已成功用于甲状腺癌 60 多年。我们小组分离了编码 NIS 的 cDNA 并生成了抗 NIS 抗体。我们已经描述了甲状腺 NIS 及其调节。乳腺 NIS (mgNIS) 介导哺乳期乳腺细胞中的主动 I- 转运，I- 从该细胞通过不同的转运蛋白被动转运至乳汁。 mgNIS 在哺乳期（而非非哺乳期）MG 中表达。 mgNIS 受雌激素、催乳素和催产素调节。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 中有多少百分比是有功能的。正常非哺乳期人类乳腺样本不表达 mgNIS。乳腺癌中 NIS 的内源表达比其他癌症具有巨大优势，其中一些癌症中 NIS 已通过病毒介导的基因转移异位表达。为了表征乳腺细胞中的 mgNIS 并确定其在乳腺癌诊断和治疗中的潜在价值，我们建议： 1. a) 表征乳腺细胞系中 mgNIS 的调节； b) 研究全身和局部调控因素对体内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-转运蛋白的作用来补充我们对哺乳期乳腺中 I-易位的理解。 2) 制定放射性碘治疗方案并评估其在动物模型中治疗腺癌的有效性。 3) 确定人类原发性乳腺肿瘤和转移瘤的细针抽吸物中 mgNIS 的功能表达及其与其他乳腺癌参数的可能相关性。