EGF RECEPTOR ECTODOMAIN AND BREAST CANCER

EGF 受体胞外域与乳腺癌

• 批准号: 2149387
• 负责人: Jeffrey E Kudlow
• 金额: $ 12.68万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2149387
• 关键词: athymic mouse; autocrine; biological signal transduction; breast neoplasms; cell growth regulation; epidermal growth factor; female; gene expression; genetically modified animals; growth factor receptors; growth inhibitors; histogenesis; immunoprecipitation; laboratory mouse; mammary gland; neoplastic cell; neoplastic process; northern blottings; protein structure function; protein tyrosine kinase; receptor binding; receptor expression; reporter genes; tissue /cell culture; transforming growth factors

The EGF system, perhaps in concert with other growth factor systems, plays a central role in human breast cancer. Levels of expression of the EGF receptor have been inversely correlated with the prognosis of the disease in humans and transgenic animals that overexpress one of the ligands for this receptor, TGFalpha, develop epithelial hyperplasia and carcinoma in the mammary gland. Estrogen regulation of breast cancer cell growth has also been partially attributed to the ability of this hormone to upregulate TGRalpha gene expression. Signaling through the EGF system may be under other complex controls. One such control could derive from regulation of the ability of the EGF receptor to signal in response to ligands. For some years, it has been appreciated that an alternate form of EGF receptor consisting of a soluble extracellular domain (ectodomain) is expressed by cancer cells and normal tissues. This segment of the receptor can bind ligand and may even be able to interact with the classical transmembrane receptor-tyrosine kinase to modulate ligand induced signal transduction. The ectodomain is produced as a result of alternate splicing of the EGF receptor transcript. We propose to study the EGF receptor ectodomain as a potential modulator of breast cancer growth and mammary gland development. We have produced milligram quantities of this molecule in a vaccinia virus system and have purified it to near homogeneity on a monoclonal antibody column. We will study the effect of this reagent on breast cancer cell growth in culture and correlate these effects with those on EGF receptor signal transduction. We will also study the effect of the ectodomain on the progression of human breast cancer in nude mice. Finally, we propose to create a transgenic mouse model in which overexpression of the ectodomain is targeted to the mammary gland using the MMTV-LTR as a promoter. These studies will form the basis for understanding the role of the EGF receptor signalling system in mammary gland development and breast cancer progression. This basic knowledge has the potential of developing into clinical applications for breast cancer and should be superior to the current protocols of using mouse derived monoclonal antibodies to the EGF receptor. This advantage relates to the observation that the EGF receptor ectodomain is a normal product of the EGF receptor gene.

EGF 系统可能与其他生长因子系统一起发挥作用 在人类乳腺癌中发挥核心作用。 EGF 的表达水平 受体与疾病的预后呈负相关 在人类和转基因动物中过度表达配体之一 这种受体，TGFα，在细胞中发展上皮增生和癌 乳腺。雌激素对乳腺癌细胞生长的调节 也部分归因于这种激素的能力 上调 TGRalpha 基因表达。通过 EGF 系统发出的信号可能 处于其他复杂的控制之下。一种这样的控制可以源自 调节 EGF 受体响应信号的能力 配体。多年来，人们已经认识到，有一种替代形式 EGF 受体由可溶性胞外域（胞外域）组成 由癌细胞和正常组织表达。受体的这个片段 可以结合配体，甚至可以与经典相互作用 跨膜受体酪氨酸激酶调节配体诱导信号 转导。胞外域是由于交替剪接而产生的 EGF 受体转录本。我们建议研究EGF受体 胞外域作为乳腺癌生长和乳腺的潜在调节剂 腺体发育。我们已经生产了毫克量的这种分子 并在痘苗病毒系统中将其纯化至接近均质 单克隆抗体柱。我们将研究该试剂对 培养中的乳腺癌细胞生长并将这些影响与 那些关于EGF受体信号转导的。我们也来研究一下效果 胞外域对裸鼠人乳腺癌进展的影响。 最后，我们建议创建一个转基因小鼠模型，其中 使用胞外域的过度表达靶向乳腺 MMTV-LTR 作为发起人。这些研究将构成基础 了解 EGF 受体信号系统在乳腺中的作用 腺体发育和乳腺癌进展。这些基础知识有 开发乳腺癌临床应用的潜力 并且应该优于当前使用鼠标衍生的协议 EGF 受体的单克隆抗体。这一优势与 观察发现 EGF 受体胞外域是 EGF 受体胞外域的正常产物 EGF受体基因。