FAK and Breast Cancer

FAK 和乳腺癌

• 批准号: 6634029
• 负责人: MICHAEL D SCHALLER
• 金额: $ 22.92万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6634029
• 关键词: actin binding protein; apoptosis; athymic mouse; breast neoplasms; cell migration; chimeric proteins; disease /disorder model; epidermal growth factor; focal adhesion kinase; genetic promoter element; genetically modified animals; growth factor receptors; immunofluorescence technique; inositol phosphates; integrins; metastasis; model design /development; mouse mammary tumor virus; neoplasm /cancer invasiveness; paxillin; recombinant proteins; viral carcinogenesis; yeast two hybrid system

DESCRIPTION (Provided by Applicant): FAK is a protein tyrosine kinase (PTK) that localizes to focal adhesions and is regulated by cell surface receptors called integrins. The ability of FAK to localize to focal adhesions is essential for its regulation and for transmission of downstream signals. FAK functions in regulating cell motility and transmits an adhesion-dependent cell survival signal. FAK may be involved in human cancer since: i) it was isolated as a Src associated substrate and activated Src has been described in human tumors. ii) changes in expression of integrins have dramatic effects upon the malignant phenotypes of cancer cells, and iii) FAK is overexpressed in some human tumors. Thus the analysis of basic FAK function and establishment of model systems of FAK overexpression may yield valuable information about the development of cancer. The current project has four main objectives: 1) to identify the binding partners that target FAK to focal adhesions. A microinjection strategy will be applied to test the role of known FAK binding partners to function in targeting. In addition, talin-/- cells will be utilized to address the role of talin in FAK targeting. Strategies to isolate novel binding partners are presented. 2) Breast epithelial cell models will be used to test the role of FAK in the acquisition of cancerous phenotypes. Wild type and activated FAK will be expressed in the MCF-10A and HCII normal breast epithelial cell lines and the phenotypes observed to determine if any parameters of oncogenic transformation have been acquired. The dominant negative FAK variant, FRNK, has been expressed in the T47D breast cancer cell line. This system will be used to assess the role of FAK in maintaining the cancerous phenotypes of these cells. 3) The crosstalk between integrin/FAK signaling pathways and growth factor receptor signaling pathways, specifically the EGF receptor family, in breast epithelial cells will be examined. Since the signaling via the EGF receptor family of PTKs is strongly linked to breast cancer the interplay between FAK and these signaling pathways may be highly significant in the pathogenesis of breast cancer. 4) Finally, a transgenic mouse model of FAK overexpression in the epithelium of the mammary gland will be established to assess its role in the development of mammary tumors in vivo. Expression of wild type and activated FAK will be targeted to mammary gland using the MMTV promoter. Mice will be examined for normal gland development and the formation and metastasis of mammary gland tumors. Genetic interactions between FAK and the Src and Neu oncogenes in the development of mammary tumors will also be examined.

描述(申请人提供)：FAK是一种蛋白酪氨酸激酶(PTK) 定位于局部粘连，并受细胞表面受体调节 叫做整合素。FAK定位于灶性粘连的能力是 对于它的调节和下行信号的传输是必不可少的。FAK 在调节细胞运动和传递黏附依赖细胞中的作用 求生信号。FAK可能与人类癌症有关，因为：i)它是分离出来的 作为一种与Src相关的底物和活化的Src已经在人类 肿瘤。Ii)整合素表达的变化对 癌细胞的恶性表型，以及III)FAK在一些 人类肿瘤。从而分析了FAK的基本功能，并建立了 FAK过表达的模型系统可能会提供关于FAK过表达的有价值的信息 癌症的发展。目前的项目有四个主要目标：1) 确定针对FAK与焦点粘连的结合伙伴。一个 微注射策略将用于测试已知FAK结合的作用 合作伙伴在目标定位方面发挥作用。此外，还将利用Talin-/-cell 以解决talin在FAK靶向中的作用。隔离小说的策略 介绍了结合伙伴的存在。2)将使用乳腺上皮细胞模型 检测FAK在获得癌变表型中的作用。野生型 并且激活的FAK将在MCF-10A和HCII正常乳腺中表达 上皮细胞系和观察的表型以确定是否有 获得了致癌转化的参数。占主导地位的 在T47D乳腺癌细胞中已经表达了FAK阴性变异体frnk。 排队。该系统将用于评估哥伦比亚革命武装力量在维持 这些细胞的癌变表型。3)整合素/FAK之间的串扰 信号通路和生长因子受体信号通路，特别是 乳房上皮细胞中的EGF受体家族将被检测。自.以来 通过EGF受体家族的PTK信号与乳房密切相关 癌症FAK和这些信号通路之间的相互作用可能高度 在乳腺癌的发病机制中具有重要意义。4)最后，转基因 FAK在乳腺上皮细胞过度表达的小鼠模型 以评估其在体内乳腺肿瘤发展中的作用。 野生型和激活的FAK将靶向乳腺表达 使用MMTV的发起人。将对小鼠进行正常的腺体发育和 乳腺肿瘤的形成和转移。遗传互作 FAK与Src、Neu癌基因在乳腺肿瘤发生发展中的关系 还将接受检查。