乳腺癌是美国妇女癌症死亡的第二大原因。许多这样的死亡发生在还只是初步诊断为侵袭性或转移性癌症之时。大量的研究证实，一种称作NEDD9的蛋白质参与调控了细胞迁移、分裂及存活，与多种癌症的肿瘤侵袭及转移有关。
近日来自Fox Chase癌症中心的研究人员发现，NEDD9通过控制引起肿瘤的祖细胞生长，在乳腺癌形成的早期阶段发挥了令人惊奇的作用。研究结果在线发表在1月14日的《癌基因》（Oncogene）杂志上，有可能为乳腺癌妇女开发出基于肿瘤中的NEDD9水平的个体化治疗新策略。
论文的资深作者是Fox Chase癌症中心的副首席执行官及副主席Erica A. Golemis博士。“多年来，人们一直认为NEDD9与晚期阶段的肿瘤转移和侵袭相关。本研究第一次揭示了NEDD9在乳腺癌的肿瘤发生中起重要的作用，并且将这一起始过程与祖细胞关联到一起，”论文的主要作者、Golemis实验室博士后研究员Joy Little说。
在这项研究中，Little、Golemis及合作者将无NEDD9基因的小鼠与形成HER2+乳腺肿瘤的转基因小鼠进行交配，发现这些小鼠大多对抗肿瘤形成。只有18%的小鼠形成了乳腺肿瘤，相比之下具有功能性NEDD9基因的小鼠则有80%的形成了乳腺肿瘤。过去的研究发现NEDD9水平增高可以促进肿瘤侵袭性，而在新研究中研究人员发现NEDD9丧失对于肿瘤转移影响不大，表明在这一特殊背景下它并非是这一过程的必要条件。肿瘤一旦形成，缺乏NEDD9的小鼠肿瘤生长迅速，表明它或是在肿瘤生长的晚期阶段起不太重要的作用，或是肿瘤发生了代偿性改变，使得它们绕过了对NEDD9的需求。
更为重要的是，研究人员发现与具有功能性NEDD9基因的小鼠相比，缺失NEDD9的小鼠乳腺中的祖细胞群数量显着减少。来自NEDD9缺失小鼠的祖细胞不太可能在培养物中形成三维微球体，而增殖速率则与来自对照小鼠的祖细胞相同。Nedd9缺失也使得祖细胞对于低剂量的两种肿瘤抑制药物更为敏感。这两种药物分别是获得FDA批准的Src抑制剂dasatinib，以及当前正在癌症治疗临床实验中进行测试的一种FAK抑制剂。这些结果表明这些类型的药物可以更有效控制低水平NEDD9乳腺癌肿瘤。
Little 说：“最终，利用活检，你或许能够读取出一个肿瘤所具有的所有突变，每一个突变都有可能表明某一线治疗是否会对一种特定的肿瘤起作用。如果在一种特定的肿瘤中NEDD9水平较高，我们有可能能够确定它是否会对某些抑制剂更加的敏感。”
为了跟进这项工作，研究人员计划进一步研究NEDD9控制肿瘤形成的机制，并调查NEDD9是否在其他的癌症中起相似的作用。(生物谷Bioon.com)
doi:10.1038/onc.2012.607
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A requirement for Nedd9 in luminal progenitor cells prior to mammary tumorigenesis in MMTV-HER2/ErbB2 mice
J L Little, V Serzhanova, E Izumchenko, B L Egleston, E Parise, A J Klein-Szanto, G Loudon, M Shubina, S Seo, M Kurokawa, M F Ochsand E A Golemis
Overexpression of the NEDD9/HEF1/Cas-L scaffolding protein is frequent, and drives invasion and metastasis in breast, head and neck, colorectal, melanoma, lung and other types of cancer. We have examined the consequences of genetic ablation of Nedd9 in the MMTV-HER2/ERBB2/neu mouse mammary tumor model. Unexpectedly, we found that only a limited effect on metastasis in MMTV-neu;Nedd9−/− mice compared with MMTV-neu;Nedd9+/+mice, but instead a dramatic reduction in tumor incidence (18 versus 80%), and a significantly increased latency until tumor appearance. Orthotopic reinjection and tail-vein injection of cells arising from tumors, coupled with in vivo analysis, indicated tumors arising in MMTV-neu;Nedd9−/− mice had undergone mutational selection that overcame the initial requirement for Nedd9. To better understand the defects in early tumor growth, we compared mammary progenitor cell pools from MMTV-neu;Nedd9−/− versus MMTV-neu;Nedd9+/+ mice. The MMTV-neu;Nedd9−/− genotype selectively reduced both the number and colony-forming potential of mammary luminal epithelial progenitor cells, while not affecting basal epithelial progenitors. MMTV-neu;Nedd9−/− mammospheres had striking defects in morphology and cell polarity. All of these defects were seen predominantly in the context of the HER2/neu oncogene, and were not associated with randomization of the plane of mitotic division, but rather with depressed expression the cell attachment protein FAK, accompanied by increased sensitivity to small molecule inhibitors of FAK and SRC. Surprisingly, in spite of these significant differences, only minimal changes were observed in the gene expression profile of Nedd9−/− mice, indicating critical Nedd9-dependent differences in cell growth properties were mediated via post-transcriptional regulation of cell signaling. Coupled with emerging data indicating a role for NEDD9 in progenitor cell populations during the morphogenesis of other tissues, these results indicate a functional requirement for NEDD9 in the growth of mammary cancer progenitor cells.
