HEREGULIN (GP30) IN BREAST CANCER TUMOR PROGRESSION

癌细胞的生长，特别是乳腺癌的生长 在许多情况下，依赖于称为生长因子的小蛋白质， 结合并激活它们的生长因子受体。其中一个增长 因子受体是erbB-2受体，它在 乳腺癌的预后和表达在非常高的水平， 近30%的人类乳腺癌患者。我们最近发现 gp 30/heregulin/NDF使我们能够识别一些相关的，但 不同的生物学终点， 通过erbB-2/4受体转导。这些生长的终点， 入侵性和分化对人类的 出现、维持和/或控制恶性肿瘤，并代表 评估人类恶性进展的既定终点 乳腺癌体外的初步研究表明，gp 3 O诱导了一种新的免疫抑制剂， 对erbB-2过表达细胞的双相生长效应。引人注目的是，我们 我最近观察到erbB-2信号通路可以被调节， 雌激素通过雌激素受体（ER）起作用。相反，我们 观察到雌激素对erbB-2的下调可被gp 3 O阻断， 通过erbB-2受体起作用。很明显， erbB-2/4/gp 3 O相互作用需要从治疗 观点，并可能进一步提供额外的见解治疗 协同作用，或增强治疗方案，为大 妇女人数。了解这些机制 互动的发生将提供一个合理的框架，我们检查 相互作用的治疗相关性，并可能有助于暴露其他 治疗目标这些机制将首先使用 体外细胞培养和生化系统。最终，我们希望这些 实验将促进erbB-2靶向治疗的出现。我们 最近确定了gp 3 O的蛋白质序列，并获得了其完整的 长度cDNA序列。此外，我们还克隆了另外两种形式， 被认为是选择性剪接的分子。我们目前正在 表达这些不同的形式，以确定它们的生物学特性， 方面的影响. gp 3 O全长cDNA的获得将为进一步研究gp 3 O的功能提供工具。 我们需要更好地了解 erbB-2癌基因产物及其在乳腺癌中的意义的 建议的研究旨在确定gp 3 O在乳腺癌中的相关性， 癌症肿瘤进展。具体而言，我们会：（一）研究规管 gp 3 O受激素、抗激素和分化因子的影响，2）测定 如果由gp 30/heregulin引起的erbB-2/4的组成性激活可以绕过 雌激素反应性乳腺癌细胞的正常雌激素需求，3） 定义gp 3 O诱导乳腺癌细胞成为 激素非依赖性和获得激素抵抗的机制 表型，4）确定erbB-2/4活化的破坏是否可以 恢复激素依赖，5）鉴定分离和克隆基因， 与gp 3 O诱导的更具侵袭性的表型有关。我们 相信这些体外和体内研究的结果可以提供 乳腺癌诊断、预后和治疗的新见解。

The growth of cancer cells in general and of breast cancer in particular depends, in many cases, upon small proteins termed growth factors that will bind and then activate their growth factor receptors. One of these growth factor receptors is the erbB-2 receptor which plays an important role in the prognosis of breast cancer and is expressed at very high levels in nearly 30% of human breast cancer patients. Our recent discovery of gp30/heregulin/NDF has allow us to identify a number of related but distinct biological endpoints which appear responsive to signal transduction through the erbB-2/4 receptor. These endpoints of growth, invasiveness, and differentiation have clear implications for the emergence, maintenance and\or control of malignancy, and represent established endpoints in the assessment of malignant progression in human breast cancer. Preliminary studies in vitro have shown that gp3O induces a biphasic growth effect on cells with erbB-2 over-expression. Strikingly, we have recently observed that the erbB-2 signalling pathway can be modulated by estrogen acting through the estrogen receptor (ER). Conversely, we observed that down regulation of erbB-2 by estrogen can be blocked by gp3O acting through the erbB-2 receptor. Clearly, mechanistic aspects of the erbB-2/4/gp3O interaction need to be understood from a therapeutic standpoint, and may furthermore provide additional insights into treatment synergy for certain patients, or enhance treatment regimens for a large number of women. Understanding the mechanism(s) through which these interactions occur will provide a rational framework with which we examine the therapeutic relevance of the interaction, and may serve to expose other therapeutic targets. These mechanisms will be examined initially using in vitro cell culture and biochemical systems. Ultimately, we hope that these experiments will facilitate the emergence of erbB-2-targeted therapy. We have recently determined the protein sequence of gp3O and obtained its full length cDNA sequence. In addition, we have cloned two additional forms that are believed to be alternatively spliced molecules. We are currently expressing these different forms, in order to determine their biological effects. The availability of gp3O full length cDNA will provide the tools we need to acquire a better understanding of the mechanism of action of the erbB-2 oncogene product and the significance of erbBA in breast cancer. The proposed studies are designed to define the relevance of gp3O in breast cancer tumor progression. Specifically, we will: l) Study the regulation of gp3O by hormones, anti-hormones and differentiation factors, 2) determine if constitutive activation of erbB-2/4 by gp30/heregulin can bypass the normal estrogen requirement of estrogen responsive breast cancer cells, 3) define the mechanism by which gp3O induces breast cancer cells to became hormone independent and to the mechanism of acquiring an hormone resistant phenotype, 4) determine if disruption of the erbB-2/4 activation can restore hormone dependence, and 5) identify isolate and clone genes that are associated with gp3O induction of a more aggressive phenotype. We believe that results from these in vitro and in vivo studies may provide new insights into breast cancer diagnosis, prognosis and treatment.