Role of Metastatic Tumor Antigen-1 in Mammary Gland

转移性肿瘤抗原 1 在乳腺中的作用

• 批准号: 6682968
• 负责人: RAKESH KUMAR
• 金额: $ 26.88万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6682968
• 关键词: breast neoplasms; carcinogenesis; carcinoma; cell line; cyclins; disease /disorder etiology; disease /disorder model; gene expression; genetic regulation; genetically modified animals; hormone related neoplasm /cancer; human tissue; laboratory mouse; mammary gland; neoplasm /cancer genetics; neoplastic cell; reproductive development; tumor antigens

DESCRIPTION (provided by applicant): The ability of the mammary gland to undergo tumorigenesis is influenced by its normal development, including reproductive endocrine events. It is increasingly accepted that mammary gland development and tumorigenesis are fundamentally linked, and perturbations in the expression or function of steroidal coactivators and corepressors or its associated targets can contribute to the etiology of steroidal cancers. We propose here to investigate the influence of metastatic tumor antigen 1 (MTA1) on the reproductive biology of the mammary gland using in vitro, transgenic mouse models, and potential roles of MTA1 and a naturally occurring variant MTA1s in the early stages of breast cancer development. In addition, cyclin D1, an established oncogene and regulator of cell cycle progression, is a common downstream target of diverse upstream signals with a role in mammary gland development and tumorigenesis. Here we propose to investigate the influence of MTA1 and its downstream target cyclin D1 on the reproductive endocrinology and development of the mammary gland and early stages of breast tumor formation using novel model systems and human tumor specimens. The rationale for this proposal is based on Preliminary data by the PI showing that MTA1 promotes anchorage-independent growth, and upregulate cyclin D1 expression. A naturally occurring spliced variant known as "MTA1s" sequesters ER in the cytoplasm and stimulates anchorage-independent growth and tumorigenicity of breast cancer cells. MMTV-MTA1 transgene expression in a mouse model results in abnormal lateral branching and alveolar development, increased cyclin D1, and hyperplastic nodules in mammary glands from virgin females. We interpret these findings as suggesting that MTA1 may have significant roles in normal mammary development by controlling expression and consequently, functions of its putative target genes such as cyclin DI. Our working hypotheses are that MTA1 play regulatory functions during normal mammary gland development and that deregulation of the MTA1 may induce alterations including, upregulation of cyclin D1 pathway, involved in early stages of breast tumor development. The specific aims of this proposal are to study: (1) The influence of MTA1 transgene expression on the biology, development and tumorigenesis of mammary gland; (2) The mechanistic role of cyclin D1 in the action of MTA1 and whether these two proteins cooperate during mouse mammary gland tumorigenesis; (3) The expression characteristics of MTA1 and MTAls and cyclin D1 during multi-step pathogenesis of breast carcinoma and to evaluate its prognostic value in-patients with invasive breast cancer. An innovative aspect of this proposal is the use of novel models to gain insights about the roles of MTA1 and MTA1s as critical pathways in the reproductive biology of mammary gland in the pathophysiologically relevant experimental setting.

描述（由申请人提供）：乳腺发生肿瘤的能力受到其正常发育的影响，包括生殖内分泌事件。人们越来越多地认识到，乳腺发育和肿瘤发生之间存在根本联系，类固醇共激活剂和辅阻遏物或其相关靶标的表达或功能的扰动可能有助于类固醇癌症的病因学。我们在此建议利用体外转基因小鼠模型研究转移性肿瘤抗原 1 (MTA1) 对乳腺生殖生物学的影响，以及 MTA1 和自然发生的变体 MTA1 在乳腺癌发展早期的潜在作用。此外，细胞周期蛋白 D1 是一种已确定的癌基因和细胞周期进程的调节因子，是多种上游信号的常见下游靶标，在乳腺发育和肿瘤发生中发挥作用。在这里，我们建议使用新型模型系统和人类肿瘤标本研究MTA1及其下游靶细胞周期蛋白D1对生殖内分泌、乳腺发育以及乳腺肿瘤形成早期的影响。 该提议的基本原理基于 PI 的初步数据，该数据表明 MTA1 促进锚定独立生长，并上调细胞周期蛋白 D1 表达。一种称为“MTA1”的天然剪接变体将 ER 隔离在细胞质中，并刺激乳腺癌细胞的贴壁依赖性生长和致瘤性。小鼠模型中的 MMTV-MTA1 转基因表达导致侧枝和肺泡发育异常、细胞周期蛋白 D1 增加以及处女乳腺中的增生结节。 我们将这些发现解释为表明 MTA1 可能通过控制其假定靶基因（如细胞周期蛋白 DI）的表达及其功能，在正常乳腺发育中发挥重要作用。我们的工作假设是，MTA1 在正常乳腺发育过程中发挥调节功能，MTA1 的失调可能会引起变化，包括细胞周期蛋白 D1 通路上调，参与乳腺肿瘤发展的早期阶段。本课题的具体目的是研究：（1）MTA1转基因表达对乳腺生物学、发育和肿瘤发生的影响； (2) cyclin D1在MTA1作用中的作用机制以及这两种蛋白在小鼠乳腺肿瘤发生过程中是否协同作用； (3)MTA1、MTAls和cyclin D1在乳腺癌多步发病过程中的表达特征及其对浸润性乳腺癌患者预后的评估价值。该提案的一个创新方面是使用新模型来深入了解 MTA1 和 MTA1 在病理生理学相关实验环境中作为乳腺生殖生物学关键途径的作用。