Role of Metastatic Tumor Antigen-1 in Mammary Gland

描述（由申请方提供）：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。人们越来越认识到乳腺发育和肿瘤发生之间存在根本联系，类固醇辅激活因子和辅抑制因子或其相关靶点的表达或功能的干扰可能导致类固醇癌症的病因。我们建议在这里调查的影响，转移性肿瘤抗原1（MTA 1）对乳腺的生殖生物学在体外，转基因小鼠模型，和潜在的作用，MTA 1和自然发生的变异MTA 1 s在乳腺癌发展的早期阶段。此外，细胞周期蛋白D1，一个既定的癌基因和细胞周期进程的调节因子，是一个共同的下游目标的不同上游信号与乳腺发育和肿瘤发生的作用。在这里，我们建议调查的影响，MTA 1和其下游的目标细胞周期蛋白D1的生殖内分泌和发展的乳腺和乳腺肿瘤形成的早期阶段，使用新的模型系统和人类肿瘤标本。 该提议的基本原理是基于PI的初步数据，显示MTA 1促进锚定非依赖性生长，并上调细胞周期蛋白D1表达。一种天然存在的剪接变体称为“MTA 1”，将ER隔离在细胞质中，并刺激乳腺癌细胞的锚定非依赖性生长和致瘤性。MMTV-MTA 1转基因在小鼠模型中的表达导致异常的侧向分支和肺泡发育、增加的细胞周期蛋白D1和来自处女雌性的乳腺中的增生性结节。 我们解释这些研究结果表明，MTA 1可能有显着的作用，在正常的乳腺发育，通过控制表达，因此，其假定的靶基因，如细胞周期蛋白DI的功能。我们的工作假设是，MTA 1在正常乳腺发育过程中发挥调节功能，MTA 1的失调可能会引起改变，包括细胞周期蛋白D1通路的上调，参与乳腺肿瘤的早期发展阶段。本课题的具体目的是研究：（1）MTA 1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MTA 1作用中的机制，以及在小鼠乳腺肿瘤发生过程中这两种蛋白是否协同作用;（3）探讨乳腺癌多阶段发病过程中MTA 1、MTA 1 s和cyclin D1的表达特点及其对浸润性乳腺癌预后的价值。该提案的一个创新方面是使用新的模型来深入了解MTA 1和MTA 1 s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。

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.