Mammary Epithelial-Specific Disruption of Focal Adhesion Kinase Retards Tumor Formation and Metastasis in a Transgenic Mouse Model of Human Breast Cancer
Mammary Epithelial-Specific Disruption of Focal Adhesion Kinase Retards Tumor Formation and Metastasis in a Transgenic Mouse Model of Human Breast Cancer
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DOI：
10.2353/ajpath.2008.080308
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发表时间：
2008-11-01
影响因子：
6
通讯作者：
Keely, Patricia J.
中科院分区：
文献类型：
--
作者：
Provenzano, Paolo P.;Inman, David R.;Keely, Patricia J.
粘着斑激酶（FAK）是粘着斑的中心调节因子，影响细胞增殖、存活和迁移。尽管有证据表明FAK在人类癌症中过表达，但其在肿瘤发生和进展中的作用尚不清楚。使用Cre/LoxP技术特异性敲除乳腺上皮中的FAK，我们表明FAK不是肿瘤起始所需的，但却是肿瘤进展所需的。这些结果的机制基础表明，FAK调节与肿瘤进展和转移相关的临床相关基因特征和多种信号复合物，如Src，ERK和p130 Cas。此外，系统水平的分析确定FAK作为肿瘤转录组的主要调节因子，影响与粘附和生长因子信号通路相关的基因及其串扰。此外，FAK被证明下调临床相关的增殖和转移相关基因的表达，以及与细胞周期的G（2）和G（2）/M期相关的基因的富集组。计算分析的转录因子结合位点内的本体丰富的或成簇的基因集表明，模具差异表达的增殖和转移相关的基因在FAK空细胞通过一组共同的转录因子，包括p53的调节。因此，FAK在转化的运动细胞中作为激活的信号网络中的主要节点，并且是治疗侵袭性人乳腺癌的新型治疗干预的主要候选者。(Am J Pathol 2008，173：1551-1565; DOI：10.2353/ajpath.2008.080308）
Focal adhesion kinase (FAK) is a central regulator of the focal adhesion, influencing cell proliferation, survival, and migration. Despite evidence demonstrating FAK overexpression in human cancer, its role in tumor initiation and progression is not well understood. Using Cre/LoxP technology to specifically knockout FAK in the mammary epithelium, we showed that FAK is not required for tumor initiation but is required for tumor progression. The mechanistic underpinnings of these results suggested that FAK regulates clinically relevant gene signatures and multiple signaling complexes associated with tumor progression and metastasis, such as Src, ERK, and p130Cas. Furthermore, a systems-level analysis identified FAK as a major regulator of the tumor transcriptome, influencing genes associated with adhesion and growth factor signaling pathways, and their cross talk. Additionally, FAK was shown to down-regulate the expression of clinically relevant proliferation-and metastasis-associated gene signatures, as well as an enriched group of genes associated with the G(2) and G(2)/M phases of the cell cycle. Computational analysis of transcription factor-binding sites within ontology-enriched or clustered gene sets suggested that die differentially expressed proliferation-and metastasis-associated genes in FAK-null cells were regulated through a common set of transcription factors, including p53. Therefore, FAK acts as a primary node in the activated signaling network in transformed motile cells and is a prime candidate for novel therapeutic interventions to treat aggressive human breast cancers. (Am J Pathol 2008,173:1551-1565; DOI: 10.2353/ajpath.2008.080308)