Role of an Epithelial Ets Factor in Breast Cancer

上皮 ETS 因子在乳腺癌中的作用

• 批准号: 6674880
• 负责人: Dennis K Watson
• 金额: $ 32.49万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 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/6674880
• 关键词: breast neoplasms; cell line; cell migration; cell motility; clinical research; female; gene expression; genetically modified animals; human subject; laboratory mouse; metastasis; neoplasm /cancer genetics; neoplasm /cancer invasiveness; neoplastic process; oncogenes; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): The long-term goal of this project is the elucidation of the mechanisms whereby Ets upstream effectors and downstream target genes contribute to progression to invasive breast cancer. Breast cancer is the second leading cause of cancer mortality in women. Unfortunately, little is known about the most devastating phase of its progression, metastasis. To metastasize, cells acquire topic motility and invasiveness as well as the ability to proliferate in a new microenvironment. Metastasis is a multi-step process, including breaking loose from cell-cell contacts, migrating through stromal tissues, invading endothelial cell layer, re-establishing and maintaining cell contacts at the metastatic site, remaining proliferative. Recently, a novel ETS factor, PDEF, was cloned and initially reported to be specific to prostate epithelium q2rostate derived ets factor). Our work has demonstrated that PDEF is expressed in several additional epithelial tissues including breast and colon. We also show that PDEF protein loss is correlated with prostate, colon and breast cancer progression. To support the model that PDEF has a central role in modulating metastatic potential, we have demonstrated that PDEF protein expression is lost in highly metastatic cell lines and in invasive breast tumor tissues. Re-expression of Pdef into invasive cancer cells inhibits cell growth. Mouse Pdef is down-regulated in tumors in Neu transgenic mice. Pdef activates the tumor metastasis suppressor maspin while downregulating the metastasis promoter uPA. The Drosophila PDEF homolog is a negative modulator of cell migration and invasion during development. Thus, our observations lead us to propose that PDEF, as a transcription factor, controls multiple aspects of the multistep metastatic process and therefore, loss of PDEF expression is a key event in the development of invasive breast cancer. In this proposal, we employ a comprehensive strategy to elucidate PDEF function, integrating four in vitro and in vivo experimental systems. (1) Cell culture for studying cellular phenotypes associated with PDEF expression levels and for identifying downstream effectors of PDEF functions. (2) Mouse knockout and transgenic systems for analyzing the role of the Pdefgene in mammary development and cancer. (3) The Drosophila system to investigate the function of Pdef in cell migration/invasion in vivo. (4) Human breast tumor samples for correlating expression of PDEF and its effectors with cancer progression.

描述(申请人提供)：该项目的长期目标是阐明ETS上游效应基因和下游靶基因促进浸润性乳腺癌进展的机制。乳腺癌是女性癌症死亡的第二大原因。不幸的是，人们对其进展过程中最具破坏性的阶段--转移知之甚少。为了转移，细胞获得了移动性和侵袭性，以及在新的微环境中增殖的能力。转移是一个多步骤的过程，包括打破细胞与细胞之间的接触，通过间质组织迁移，侵入内皮细胞层，在转移部位重新建立和维持细胞接触，保持增殖。最近，一种新的ETS因子PDEF被克隆出来，并被首次报道为前列腺上皮细胞所特有的。我们的工作表明，PDEF在包括乳腺和结肠在内的其他几种上皮组织中都有表达。我们还表明，PDEF蛋白丢失与前列腺癌、结肠癌和乳腺癌的进展相关。为了支持PDEF在调节转移潜能中起中心作用的模型，我们证明了PDEF蛋白在高转移细胞系和浸润性乳腺肿瘤组织中的表达缺失。PDEF在侵袭性癌细胞中的重新表达抑制了细胞的生长。在Neu转基因小鼠的肿瘤中，小鼠PDEF表达下调。PDEF激活肿瘤转移抑制因子maspin，同时下调转移促进因子uPA。果蝇PDEF同源基因是发育过程中细胞迁移和侵袭的负调控因子。因此，我们的观察使我们认为，PDEF作为一种转录因子，控制着多步转移过程的多个方面，因此，PDEF表达的缺失是浸润性乳腺癌发生中的一个关键事件。在这个提案中，我们采用了一个综合的策略来阐明PDEF的功能，整合了四个体外和体内的实验系统。(1)细胞培养，用于研究与PDEF表达水平相关的细胞表型，并识别PDEF功能的下游效应因子。(2)用于分析PDefgene在乳腺发育和癌症中作用的小鼠基因敲除和转基因系统。(3)果蝇系统研究PDEF在体内细胞迁移/侵袭中的作用。(4)人乳腺肿瘤组织中PDEF及其效应分子的表达与肿瘤进展的关系。