HER2 in Breast Tumor Progression and Metastasis

HER2 在乳腺肿瘤进展和转移中的作用

• 批准号: 6914929
• 负责人: MIEN-CHIE HUNG
• 金额: $ 30.96万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6914929
• 关键词: MCF7 cell; athymic mouse; breast neoplasms; chemokine receptor; gene expression; genetic regulation; metastasis; neoplasm /cancer genetics; neoplastic process; nonsteroidal antiinflammatory agent; oxidoreductase inhibitor; prostaglandin endoperoxide synthase; protein localization; protein transport; protein tyrosine kinase; protooncogene

DESCRIPTION (provided by applicant): Overexpression of HER2, a receptor tyrosine kinase (RTK) was found in approximately 30% of breast cancers and shown to correlate with the number of lymph node metastases and poor prognosis of the patients. HER2 overexpression leads to enhanced metastatic potential of breast cancer ceils, and poor clinical outcome of patients. Therefore, HER2 serves as an excellent target for the development of novel cancer therapies. Recently, CXCR4 was found to play a very important role in targeted metastasis of breast cancer. The malignant breast cancer cells are enriched for a chemokine receptor, CXCR4; and SDF-1 alpha, a natural ligand for CXCR4, is released in high amounts by certain organs, such as bone marrow, lung and liver. Our data show that HER2 can upregulate CXCR4 expression in breast cancer cells and the inhibition of CXCR4 function/or expression in HER2-overexpressing cancer cells suppresses HER2-induced malignancy. Therefore, our data provide a link between HER2 and CXCR4 in breast tumor progression and metastasis. Another important molecule COX2, a cyclooxygenase enzyme, is also involved in tumor invasion an( metastasis. Many RTKs have been found to locate in the nucleus, in spite of the fact that RTKs are traditionally known to be transmembrane cell surface proteins. Recently, using a cloning strategy for identification of targets for nuclear RTKs to understand their the biological significance and functions, we found that nuclear HER2 binds to a specific DNA element on the COX promoter and activates the promoter activity. The HER2-induced COX2 upregulation assembles the two important molecules involving in tumor progression. The long term goal of this proposal is to understand mechanisms for tumor progression and metastasis of breast cancer, specially, the roles of CXCR4 and COX2 in the HER2-mediated tumor progression and metastasis. In addition, we will investigate cellular mechanism of HER2 nuclear localization. Thus, three specific aims are proposed: Specific Aim 1: Tumor progression and metastasis of HER2-induced CXCR4 expression, Specific Aim 2: Tumor progression, metastasis and molecular mechanisms of HER2-induced COX2 expression, and Specific Aim 3: Cellular pathway for HER2 trafficking from cell surface membrane to nucleus and its effect on tumor progression and metastasis. Success of the proposal will further facilitate our better understanding in tumor progression and metastasis of breast cancer and may also provide a new avenue to comprehend functions and biological significances of nuclear RTKs, which have been overlooked in the past decades.

描述（由申请人提供）：在约30%的乳腺癌中发现了HER 2（一种受体酪氨酸激酶（RTK））的过表达，并显示与淋巴结转移的数量和患者的不良预后相关。HER 2过表达导致乳腺癌细胞的转移潜能增强，并且患者的临床结果较差。因此，HER 2是开发新型癌症疗法的极好靶点。近年来，研究发现CXCR 4在乳腺癌的靶向转移中起着非常重要的作用。恶性乳腺癌细胞富含趋化因子受体CXCR 4; SDF-1 α是CXCR 4的天然配体，由某些器官（如骨髓、肺和肝脏）大量释放。我们的数据显示，HER 2可以上调乳腺癌细胞中CXCR 4的表达，并且抑制HER 2过表达癌细胞中CXCR 4的功能/或表达可以抑制HER 2诱导的恶性肿瘤。因此，我们的数据提供了HER 2和CXCR 4在乳腺肿瘤进展和转移中的联系。另一种重要的分子COX 2，一种环氧合酶，也参与肿瘤的侵袭和转移。尽管传统上认为RTK是跨膜细胞表面蛋白，但已发现许多RTK位于细胞核中。最近，我们利用克隆策略来鉴定核RTK的靶点以了解其生物学意义和功能，发现核HER 2与考克斯启动子上的特异性DNA元件结合并激活启动子活性。HER 2诱导的COX 2上调组装了参与肿瘤进展的两个重要分子。本项目的长期目标是了解乳腺癌的肿瘤进展和转移机制，特别是CXCR 4和COX 2在HER 2介导的肿瘤进展和转移中的作用。此外，我们还将探讨HER 2核定位的细胞机制。因此，提出了三个具体目标： 具体目标1：HER 2诱导的CXCR 4表达的肿瘤进展和转移，特异性目的2：HER 2诱导的COX 2表达的肿瘤进展、转移和分子机制，特异性目的3：HER 2从细胞表面膜转运至细胞核的细胞途径及其对肿瘤进展和转移的影响。该提案的成功将进一步促进我们更好地了解乳腺癌的肿瘤进展和转移，也可能为理解核RTK的功能和生物学意义提供新的途径，这在过去几十年中一直被忽视。