Izumchenko Eugene, Singh Mahendra K, Plotnikova Olga V, Tikhmyanova Nadezhda, Little Joy L, Serebriiskii Ilya G, Seo Sachiko, Kurokawa Mineo, Egleston Brian L, Klein-Szanto Andres, Pugacheva Elena N, Hardy Richard R, Wolfson Marina, Connolly Denise C, Golemis Erica A
Program in Molecular and Translational Medicine, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Cancer Res. 2009 Sep 15;69(18):7198-206. doi: 10.1158/0008-5472.CAN-09-0795. Epub 2009 Sep 8.
In the past 3 years, altered expression of the HEF1/CAS-L/NEDD9 scaffolding protein has emerged as contributing to cancer metastasis in multiple cancer types. However, whereas some studies have identified elevated NEDD9 expression as prometastatic, other work has suggested a negative role in tumor progression. We here show that the Nedd9-null genetic background significantly limits mammary tumor initiation in the MMTV-polyoma virus middle T genetic model. Action of NEDD9 is tumor cell intrinsic, with immune cell infiltration, stroma, and angiogenesis unaffected. The majority of the late-appearing mammary tumors of MMTV-polyoma virus middle T;Nedd9(-/-) mice are characterized by depressed activation of proteins including AKT, Src, FAK, and extracellular signal-regulated kinase, emphasizing an important role of NEDD9 as a scaffolding protein for these prooncogenic proteins. Analysis of cells derived from primary Nedd9(+/+) and Nedd9(-/-) tumors showed persistently reduced FAK activation, attachment, and migration, consistent with a role for NEDD9 activation of FAK in promoting tumor aggressiveness. This study provides the first in vivo evidence of a role for NEDD9 in breast cancer progression and suggests that NEDD9 expression may provide a biomarker for tumor aggressiveness.
在过去3年中，支架蛋白HEF1/CAS-L/NEDD9表达的改变已被证明在多种癌症类型的转移中起作用。然而，一些研究认为NEDD9表达升高会促进转移，而其他研究则表明其在肿瘤进展中起负面作用。我们在此表明，Nedd9基因敲除的遗传背景在MMTV-多瘤病毒中T基因模型中显著限制乳腺肿瘤的起始。NEDD9的作用是肿瘤细胞内在性的，对免疫细胞浸润、基质和血管生成无影响。MMTV-多瘤病毒中T；Nedd9(-/-)小鼠的大多数晚期出现的乳腺肿瘤的特征是包括AKT、Src、FAK和细胞外信号调节激酶在内的蛋白质激活受到抑制，这强调了NEDD9作为这些促癌蛋白的支架蛋白的重要作用。对源自原发性Nedd9(+/+)和Nedd9(-/-)肿瘤的细胞分析显示，FAK激活、黏附和迁移持续减少，这与NEDD9激活FAK在促进肿瘤侵袭中的作用一致。本研究首次提供了NEDD9在乳腺癌进展中作用的体内证据，并表明NEDD9表达可能为肿瘤侵袭性提供一个生物标志物。
