FAK and Breast Cancer

FAK 和乳腺癌

• 批准号: 6515024
• 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/6515024
• 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.

说明（申请人提供）：FAK是一种蛋白酪氨酸激酶（PTK） 定位于粘着斑并受细胞表面受体调节 叫做整合素。FAK定位于局灶性粘连的能力是 对于其调节和下游信号的传输至关重要。FAK 在调节细胞运动中起作用，并将粘附依赖性细胞 生存信号FAK可能与人类癌症有关，因为：i）它是分离的 作为Src相关的底物和活化的Src已经在人类中被描述， 肿瘤的ii）整联蛋白表达的变化对细胞的生长有显著影响。 iii）FAK在某些癌细胞中过表达， 人类肿瘤因此，分析FAK的基本功能， FAK过表达的模型系统可能会产生关于 癌症的发展。目前的项目有四个主要目标：1） 鉴定将FAK靶向至粘着斑的结合配偶体。一 将应用显微注射策略来测试已知FAK结合的作用。 合作伙伴在目标上发挥作用。此外，将利用talin-/-细胞 来解决塔林在FAK定位中的作用。隔离小说的策略 提出了结合伙伴。2)将使用乳腺上皮细胞模型 以测试FAK在癌症表型获得中的作用。野生型 并且活化的FAK将在MCF-10A和HCII正常乳腺中表达 观察上皮细胞系和表型以确定是否存在 已获得致癌转化的参数。主导 阴性FAK变体FRNK在T47 D乳腺癌细胞中表达 线该系统将用于评估FAK在维护 这些细胞的癌性表型。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 表皮生长因子受体家族，在乳腺上皮细胞将被检查。以来 通过PTKs的EGF受体家族的信号传导与乳腺癌密切相关。 在癌症中，FAK和这些信号通路之间的相互作用可能是高度相关的。 在乳腺癌的发病机制中具有重要意义。4)最后，转基因 在乳腺上皮中FAK过表达的小鼠模型将 以评估其在体内乳腺肿瘤发展中的作用。 野生型和活化的FAK的表达将靶向乳腺 使用MMTV启动子。将检查小鼠的正常腺体发育， 乳腺肿瘤的形成和转移。遗传相互作用 FAK与Src和Neu癌基因在乳腺肿瘤发生中的关系 也将被审查。