Early events of carcinoma induced by ErbB receptors

ErbB 受体诱导的癌症早期事件

• 批准号: 6856492
• 负责人: SENTHIL K MUTHUSWAMY
• 金额: $ 37.71万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6856492
• 关键词: acinar cell; biological signal transduction; breast neoplasms; carcinogenesis; carcinoma; cell growth regulation; cell morphology; cell proliferation; cellular polarity; electron microscopy; epithelioma; growth factor receptors; immunoprecipitation; mammary epithelium; neoplastic transformation; oncogenes; protein localization; protein structure function; protein tyrosine kinase; tissue /cell culture

DESCRIPTION (provided by applicant): We know that pathogenesis of cancer begins as hyperplastic lesions, some of which progress to malignancy while other remain benign. The molecular features that differentiate lesions are largely unknown. This is in part due to lack of our understanding of the molecular mechanisms that initiate transformation of epithelial cells in vivo. Loss of growth control and disruption of epithelial architecture are thought to be earliest events in cancer. However, we do not understand how oncogenes coordinately deregulate growth control and architecture to initiate transformation of epithelial cells in vivo. Oncogenes of the ErbB receptor tyrosine kinase family can initiate transformation of epithelia in vivo. However, it has been a challenge to understand how different members of the ErbB family transform epithelial cells because they function by forming homo- and heterodimers amongst themselves, which complicates our ability to dissect out the role played by specific ErbB dimers. We have developed a novel method to control dimerization of ErbB receptors that will allow us to activate specific receptor dimers of choice in normal epithelial cells. We have also adapted a cell culture method to generate three-dimensional, polarized, growth-arrested epithelial cells that share several properties with cells lining the ducts in vivo. Combination of these two approaches provides us with novel and powerful tool to understand the molecular mechanisms by which ErbB receptors transform growth-arrested, polarized epithelial cells. Using our unique system, we will activate various combinations of ErbB receptor dimers to (1) investigate the ability of specific ErbB dimers to induce uncontrolled proliferation and loss of architecture in 3D mammary epithelial acini-like structures and identify the signaling pathways critical for this process (2) identify the mechanisms by which different ErbB homo- and heterodimers affect localization and function of proteins that regulate epithelial cell polarity, and (3) determine the relationship between the ability of ErbB dimers to disrupt cell polarity and their ability to re-initiate proliferation in growth-arrested, polarized epithelial cells. Of particular importance is our capability to uncover novel molecular mechanism involved in initiation of carcinoma and also to identify novel and specific targets for treating patients with ErbB-positive tumors.

描述（由申请人提供）：我们知道癌症的发病机理是从增生性病变开始的，其中一些病变发展为恶性肿瘤，而另一些则保持良性。区分病变的分子特征在很大程度上未知。这部分是由于我们缺乏对启动体内上皮细胞转化的分子机制的理解。丧失生长控制和上皮结构的破坏被认为是癌症中最早的事件。但是，我们不了解肿瘤基因如何协同放大生长控制和结构以启动体内上皮细胞的转化。 ERBB受体酪氨酸激酶家族的癌基因可以启动体内上皮的转化。但是，了解ERBB家族的不同成员如何改变上皮细胞是一个挑战，因为它们通过在彼此之间形成同型和异二聚体来发挥作用，这使我们剖析特定ERBB二聚体所起的作用的能力变得复杂。我们已经开发了一种新的方法来控制ERBB受体的二聚化，这将使我们能够激活正常上皮细胞中选择的特定受体二聚体。我们还适应了一种细胞培养方法来产生三维，极化，生长捕获的上皮细胞，这些细胞与体内管道内衬有多种细胞具有多种特性。这两种方法的组合为我们提供了新颖而强大的工具，以了解ERBB受体转化生长降落的极化上皮细胞的分子机制。使用我们独特的系统，我们将激活ERBB受体二聚体的各种组合，以（1）调查特定的ERBB二聚体诱导不受控制的增殖和体系结构损失的能力细胞极性和（3）确定ERBB二聚体破坏细胞极性的能力与它们在生长降落的极化上皮细胞中重点增殖的能力之间的关系。尤其重要的是，我们有能力发现涉及癌开始的新型分子机制，并确定治疗ERBB阳性肿瘤患者的新颖和特定靶标。