HER-2/NEU ALTERATIONS IN BREAST AND OVARIAN CANCER

描述（由申请人提供）：人HER-2/neu基因编码一种生长因子， 因子受体，其属于I型受体酪氨酸激酶家族。 现在人们普遍认为，这种基因的改变起着某些作用。 在25- 30%的人类乳腺癌发病机制中起着关键作用， 它的扩增和过度表达导致癌症 尤其是在病人身上。由于这一观察， 利用单克隆抗体成功地靶向了基因改变， 抗体Herceptin，其针对细胞外结构域， 受体的在支持该项目的前期， 已经鉴定出与这种改变相关的表型异常 并显示与侵袭性临床表型一致，即， 增加体外生长、增加体内致瘤性和增加 在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，仍然只是部分阐明。这是这个提议的目的 继续和扩大研究工作，旨在解剖分子 为了更好地了解这一变化的下游事件， 并可能确定分子靶点， 这种改变的治疗方法甚至更有效。为此， 将实现四个具体目标，包括。进一步的表征 HER-2/neu过表达相关的信号通路，以及HER-2/neu过表达相关的信号通路。 激动剂诱导的这些途径的相似性和差异 （heregulin，NDF）和拮抗剂（赫赛汀）;数据扩展 由特异性目的I生成，以评价PI 3激酶的变化 与AKT 2信号通路相关的信号通路， HER-2/neu表型;差异表达基因的鉴定 在HER-2过表达与匹配的非过表达细胞中，以及 用激动剂（heregulin）和拮抗剂（Herceptin）处理的细胞;和 最后，在蛋白质中鉴定的任何独特基因的表征， 细胞水平，即编码蛋白的鉴定，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，如有需要。

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.