Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Cancer Lett. 2010 Mar 28;289(2):127-39. doi: 10.1016/j.canlet.2009.07.005. Epub 2009 Jul 29.
Focal adhesion kinase (FAK) is an intracellular non-receptor tyrosine kinase. In addition to its role as a major mediator of signal transduction by integrins, FAK also participates in signaling by a wide range of extracellular stimuli including growth factors, G-protein-coupled receptor agonists, cytokines, and other inflammatory mediators. The link between FAK and breast cancers is strongly suggested by a number of reports showing that FAK gene is amplified and overexpressed in a large fraction of breast cancer specimens. In addition, increased FAK expression and activity frequently correlate with metastatic disease and poor prognosis. Since its discovery in early 1990s, numerous studies have shown a role for FAK in the regulation of cell spreading, adhesion, migration, survival, proliferation, differentiation, and angiogenesis. Many of these studies in cultured cells provided strong evidence to connect FAK expression/activation to the promotion of cancer. Recently, a prominent role of FAK in promoting mammary tumorigenesis, progression and metastasis has been unveiled by different animal models of human breast cancer, including xenograft models in immunodeficient rodents and spontaneous tumor models in transgenic mice that have specific deletion of FAK in the mammary epithelial cells during embryonic or postnatal development. These in vivo studies established FAK as a prominent determinant in mammary cancer initiation, progression and metastasis. Furthermore, a novel function of FAK in maintaining mammary cancer stem/progenitor cells in vivo has been recently reported, which may provide a novel cellular mechanism of FAK in promoting breast cancer initiation and progression. The wealth of knowledge accumulated over almost two decades of research on FAK should help to design potentially novel therapies for breast cancer.
黏着斑激酶（FAK）是一种细胞内非受体酪氨酸激酶。除了作为整合素信号转导的主要介质外，FAK 还参与由生长因子、G 蛋白偶联受体激动剂、细胞因子和其他炎症介质等多种细胞外刺激的信号转导。大量报道表明 FAK 基因在乳腺癌标本的很大一部分中扩增和过表达，这强烈提示 FAK 与乳腺癌之间存在联系。此外，FAK 表达和活性的增加常与转移疾病和预后不良相关。自 20 世纪 90 年代初发现以来，大量研究表明 FAK 在调节细胞扩展、黏附、迁移、存活、增殖、分化和血管生成方面发挥作用。许多这些在培养细胞中的研究提供了强有力的证据，将 FAK 表达/激活与癌症的促进联系起来。最近，通过不同的人类乳腺癌动物模型，包括免疫缺陷啮齿动物的异种移植模型和在胚胎或出生后发育过程中特异性缺失 FAK 的转基因小鼠的自发肿瘤模型，揭示了 FAK 在促进乳腺肿瘤发生、进展和转移中的突出作用。这些体内研究确立了 FAK 是乳腺癌症起始、进展和转移的重要决定因素。此外，最近报道了 FAK 在体内维持乳腺肿瘤干细胞/祖细胞的新功能，这可能为 FAK 促进乳腺癌起始和进展提供了新的细胞机制。近二十年来对 FAK 的研究积累了丰富的知识，应该有助于设计用于乳腺癌的潜在新型疗法。
