Role of Metastatic Tumor Antigen-1 in Mammary Gland

描述(申请人提供)：乳腺发生肿瘤的能力受其正常发育的影响，包括生殖内分泌事件。人们越来越接受的观点是，乳腺发育和肿瘤的发生有根本的联系，而类固醇辅活化子和辅抑制子或其相关靶点的表达或功能的紊乱可能与类固醇癌症的病因有关。我们建议使用体外转基因小鼠模型来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和一种自然发生的MTA1变异体在乳腺癌早期发展中的潜在作用。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，是多种上游信号的共同下游靶点，在乳腺发育和肿瘤发生中发挥作用。在这里，我们建议使用新的模型系统和人类肿瘤标本来研究MTA1及其下游靶细胞周期蛋白D1对乳腺的生殖内分泌学和发育以及乳腺肿瘤形成的早期阶段的影响。 这一建议的基本原理是基于PI的初步数据，该数据表明MTA1促进了锚定非依赖性生长，并上调了细胞周期蛋白D1的表达。一种被称为“MTA1S”的自然产生的剪接变体将ER隔离在细胞质中，并刺激乳腺癌细胞的非锚定生长和致瘤性。转基因表达MMTV-MTA1的小鼠模型导致异常的侧枝和肺泡发育，细胞周期蛋白D1增加，以及处女女性乳腺中的增生性结节。 我们对这些发现的解释是，MTA1可能通过控制其可能的靶基因的表达和功能，如细胞周期蛋白DI，在正常乳腺发育中发挥重要作用。我们的工作假设是，MTA1在正常的乳腺发育过程中发挥着调节功能，并且MTA1的解除调控可能会引起改变，包括参与乳腺肿瘤早期发展的细胞周期蛋白D1途径的上调。该建议的具体目的是研究：(1)MTA1转基因表达对乳腺的生物学、发育和肿瘤发生的影响；(2)Cyclin D1在MTA1作用中的机制作用以及这两种蛋白在小鼠乳腺肿瘤形成过程中是否协同作用；(3)MTA1、MTAls和Cyclin D1在乳腺癌多步骤发病过程中的表达特点，并评估其在浸润性乳腺癌患者中的预后价值。这项建议的一个创新方面是使用新的模型来深入了解MTA1和MTA1作为关键途径在病理生理学相关的实验环境中的乳腺生殖生物学中的作用。

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.