EGF RECEPTOR ECTODOMAIN AND BREAST CANCER

EGF系统，可能与其他生长因子系统协同发挥作用 在人类乳腺癌中起着核心作用。表皮生长因子的表达水平 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其中一种配体 这种受体，TGFpha，会导致上皮细胞增生和癌症 乳腺。雌激素对乳腺癌细胞生长的调节作用 也部分归因于这种荷尔蒙有能力 上调TGRpha基因表达。通过EGF系统的信令可以 处于其他复杂的控制之下。一个这样的控件可能派生自 表皮生长因子受体信号转导能力的调节 配基。多年来，人们一直意识到，另一种形式的 EGF受体由一个可溶性的胞外区(胞外区)组成 在癌细胞和正常组织中表达。这段受体 可以结合配体，甚至可以与经典的 跨膜受体-酪氨酸激酶对配体诱导信号的调节 转导。胞外区是交替剪接的结果 EGF受体转录本。我们建议研究EGF受体 胞外结构域作为乳腺癌生长和乳腺的潜在调节因子 腺体发育。我们已经生产了毫克量的这种分子 在痘苗病毒系统中，并已将其纯化到近乎均一的 单克隆抗体柱。我们将研究这种试剂对人体健康的影响 乳腺癌细胞在培养中的生长，并将这些效应与 关于EGF受体信号转导的研究。我们还将研究其影响 在裸鼠体内研究胞外区域对人类乳腺癌进展的影响。 最后，我们建议创建一种转基因小鼠模型，在该模型中 胞外结构域的过表达是通过使用 MMTV-LTR作为启动子。这些研究将形成以下基础 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。这些基本知识有 乳腺癌临床应用的潜力 并且应该优于当前使用鼠标派生的协议 抗EGF受体的单抗。这一优势与 观察到EGF受体胞外结构域是正常的 EGF受体基因。

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.