HER-2/NEU ALTERATIONS IN BREAST AND OVARIAN CANCER

乳腺癌和卵巢癌中的 HER-2/NEU 改变

• 批准号: 6657487
• 负责人: DENNIS J SLAMON
• 金额: $ 18.15万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-16 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6657487
• 关键词: MCF7 cell; antineoplastic antibiotics; biological signal transduction; breast neoplasms; enzyme activity; gene expression; gene mutation; growth factor receptors; heregulin; human tissue; immunocytochemistry; intravital microscopy; microarray technology; mitogen activated protein kinase; monoclonal antibody; neoplasm /cancer genetics; neoplastic transformation; northern blottings; ovary neoplasms; phosphatidylinositol 3 kinase; polymerase chain reaction; protein tyrosine kinase; protooncogene; receptor expression; transforming growth factors; vascular endothelial growth factors; western blottings

DESCRIPTION (provided by applicant): The human HER-2/neu gene encodes a growth factor receptor which belongs to the type I receptor tyrosine kinase family. It is now generally accepted that the alteration of this gene plays some critical role in the pathogenesis of the 25-30 percent of human breast cancers in which is it amplified and overexpressed causing the cancers to behave particularly aggressively in patients. As a result of this observation, this genetic alteration has been successfully targeted using the monoclonal antibody Herceptin which is directed against the extra cellular domain of the receptor. During the prior period of support of this project, many of the phenotypic abnormalities associated with this alteration have been identified and shown to be consistent with an aggressive clinical phenotype, i.e. increase growth in vitro, increased tumorigenicity in vivo and increase metastatic potential in orthotopic implantation models. The molecular pathways and mechanisms by which these phenotypic changes are mediated, however, remain only partially elucidated. It is the purpose of this proposal to continue and expand research efforts directed at dissecting the molecular events downstream of this alteration in order to gain a better understanding of this event and perhaps identify molecular targets that would make therapeutic approaches to this alteration even more effective. To that end, four specific aims will be undertaken, including. The further characterization of signaling pathways associated with HER-2/neu overexpression, as well as the similarities and differences in these pathways induced by an agonist (heregulin, NDF) and an antagonist (Herceptin); the expansion on data generated from Specific Aim I to evaluate the changes in the PI3 kinases signaling pathway related to the AKT 2 sgne which appears to be important in the HER-2/neu phenotype; the identification of differentially expressed genes in HER-2 overexpressing versus matched non-overexpressing cells, as well as cells treated with an agonist (heregulin) and antagonist (Herceptin); and finally the characterization of any unique genes identified at the protein and cellular levels, i.e. identification of the encoded protein, characterization of its half life, expression pattern in normal and malignant tissues, and functional studies if indicated.

描述（由申请人提供）：人类 HER-2/neu 基因编码生长 属于I型受体酪氨酸激酶家族的因子受体。 现在普遍认为该基因的改变起到了一定的作用 在 25-30% 人类乳腺癌的发病机制中发挥着关键作用 它在其中被扩增和过度表达，导致癌症表现 对患者尤其具有攻击性。根据这一观察结果， 使用单克隆抗体已成功靶向遗传改变 抗体赫赛汀，针对细胞外结构域 受体。在该项目的前期支持期间，许多 与这种改变相关的表型异常已被确定 并显示出与侵袭性临床表型一致，即 增加体外生长，增加体内致瘤性并增加 原位植入模型中的转移潜力。分子 介导这些表型变化的途径和机制， 然而，目前仅得到部分阐明。这就是本提案的目的 继续并扩大旨在剖析分子的研究工作 为了更好地理解这一变化的下游事件 的这一事件，也许可以确定分子目标，使 这种改变的治疗方法更加有效。为此， 将实现四个具体目标，包括：进一步表征 与 HER-2/neu 过表达相关的信号通路，以及 激动剂诱导的这些途径的相似点和差异 （调蛋白，NDF）和拮抗剂（赫赛汀）；数据的扩展 由 Specific Aim I 生成，用于评估 PI3 激酶的变化 与 AKT 2 sgne 相关的信号通路，这似乎在 HER-2/neu 表型；差异表达基因的鉴定 HER-2 过表达细胞与匹配的非过表达细胞的比较，以及 用激动剂（heregulin）和拮抗剂（赫赛汀）处理的细胞；和 最后，在蛋白质上鉴定出任何独特基因的特征 细胞水平，即编码蛋白质的鉴定、表征 其半衰期、在正常和恶性组织中的表达模式，以及 功能研究（如果有指示）。