EGF RECEPTOR ECTODOMAIN AND BREAST CANCER

EGF系统可能与其他生长因子系统一起发挥作用， 在人类乳腺癌中起着核心作用。EGF的表达水平 受体与疾病预后呈负相关 在过表达一种配体的人类和转基因动物中， 这种受体TGF α，在哺乳动物中发展为上皮增生和癌， 乳腺雌激素调节乳腺癌细胞生长 也部分归因于这种激素的能力， 上调TGR α基因表达。EGF的作用机制 在其他复杂的控制下。一种这样的控制可能来自于 EGF受体的信号传导能力 配体。几年来，人们已经认识到， EGF受体由可溶性细胞外结构域（胞外域）组成， 由癌细胞和正常组织表达。受体的这一部分 可以结合配体，甚至可以与经典的 调节配体诱导信号的跨膜受体酪氨酸激酶 转导胞外域是由选择性剪接产生的 EGF受体的作用EGF受体的研究 胞外域作为乳腺癌生长和乳腺癌细胞增殖的潜在调节剂 腺体发育我们已经生产了毫克数量的这种分子 在牛痘病毒系统中，并已将其在 单克隆抗体柱。我们将研究这种试剂对 乳腺癌细胞在培养中的生长，并将这些影响与 EGF受体信号转导我们还将研究 的胞外域对裸鼠人乳腺癌的进展。 最后，我们建议建立一个转基因小鼠模型， 胞外域的过表达靶向乳腺， MMTV-LTR作为启动子。这些研究将构成以下方面的基础： 了解EGF受体信号系统在乳腺癌中的作用 腺体发育和乳腺癌进展。这些基本知识 乳腺癌临床应用的潜力 并且应该上级目前使用小鼠衍生的 EGF受体的抗体这一优势与 观察到EGF受体胞外域是正常的产物， 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.