HER2 in Breast Tumor Progression and Metastasis

描述(申请人提供)：HER2，一种受体酪氨酸激酶(RTK)的过度表达在大约30%的乳腺癌中被发现，并被证明与淋巴转移的数量和患者的不良预后有关。HER2过表达导致乳腺癌细胞转移潜能增强，患者临床预后不良。因此，HER2是开发新的癌症治疗方法的极佳靶点。最近发现，CXCR4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CXCR4；而CXCR4的天然配体SDF-1α则由某些器官，如骨髓、肺和肝脏大量释放。我们的数据表明，HER2可以上调乳腺癌细胞中CXCR4的表达，抑制HER2过表达的癌细胞中CXCR4的功能/或表达可以抑制HER2诱导的恶性转化。因此，我们的数据提供了HER2和CXCR4在乳腺癌进展和转移中的联系。另一个重要的分子COX2，一种环氧合酶，也参与了肿瘤的侵袭和转移。许多RTK被发现位于细胞核内，尽管RTK传统上被认为是跨膜细胞表面蛋白。最近，为了了解其生物学意义和功能，我们利用克隆策略确定了核RTK的靶标，我们发现核HER2与COX启动子上的特定DNA元件结合并激活启动子的活性。HER2诱导的COX2上调聚集了参与肿瘤进展的两个重要分子。该方案的长期目标是了解乳腺癌的肿瘤进展和转移机制，特别是CXCR4和COX2在HER2介导的肿瘤进展和转移中的作用。此外，我们还将探讨HER2核定位的细胞机制。因此，提出了三个具体目标： 特异靶1：HER2诱导的CXCR4表达的肿瘤进展和转移；特异靶2：HER2诱导的COX2表达的肿瘤进展、转移及其分子机制；特异靶3：HER2从细胞膜转运到细胞核的细胞途径及其对肿瘤进展和转移的影响。该提议的成功将进一步促进我们对乳腺癌的肿瘤进展和转移的了解，也可能为理解核RTK的功能和生物学意义提供新的途径，这些功能和生物学意义在过去几十年中被忽视了。

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.