Loss of the 14-3-3σ Tumor Suppressor Is a Critical Event in ErbB2-Mediated Tumor Progression
Loss of the 14-3-3σ Tumor Suppressor Is a Critical Event in ErbB2-Mediated Tumor Progression
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DOI：
10.1158/2159-8290.cd-11-0189
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发表时间：
2012-01-01
期刊：
影响因子：
28.2
通讯作者：
Muller, William J.
中科院分区：
文献类型：
--
作者：
Ling, Chen;Vi-Minh-Tri Su;Muller, William J.
14-3-3西格玛是一种可能的肿瘤抑制因子，参与细胞周期进展和上皮细胞的极性。我们证明，条件性14-3-3西格玛等位基因的一个或两个副本的丢失会导致在内源性erbB2启动子下表达激活的erbB2癌基因的小鼠加速乳腺和唾液肿瘤的发生。值得注意的是，大多数携带单一条件性14-3-3sigma等位基因的肿瘤失去了剩余14-3-3sigma等位基因的表达，这与14-3-3sigma基因的表观遗传甲基化有关。除了加速肿瘤的发病，在小鼠乳腺肿瘤病毒驱动的ErbB2肿瘤模型中，14-3-3sigma的丢失会导致与细胞连接丢失相关的转移表型增强。综上所述，这些结果提供了令人信服的证据，表明14-3-3 sigma是一种有效的肿瘤抑制因子，参与了ErbB2驱动的乳腺癌的发生和转移。与其作为肿瘤抑制物的潜在作用一致，我们证明了在许多上皮组织中靶向干扰14-3-3sigma可以通过调节一些不同的信号网络深刻地影响ErbB2介导的肿瘤进展的起始和转移阶段。癌症发现；2(1)；68-81。(C)2011年AACR。
14-3-3 sigma is a putative tumor suppressor involved in cell-cycle progression and epithelial polarity. We demonstrate that loss of one or both copies of the conditional 14-3-3 sigma allele results in accelerated mammary and salivary tumorigenesis in mice expressing an activated erbB2 oncogene under the endogenous erbB2 promoter. Significantly, the majority of tumors bearing a single conditional 14-3-3 sigma allele lose expression of the remaining 14-3-3 sigma allele, which is associated with epigenetic methylation of the 14-3-3 sigma locus. In addition to accelerated tumor onset, in a mouse mammary tumor virus-driven ErbB2 tumor model, loss of 14-3-3 sigma results in enhanced metastatic phenotype that is correlated with loss of cellular junctions. Taken together, these results provide compelling evidence that 14-3-3 sigma is a potent tumor suppressor involved in ErbB2-driven breast cancer initiation and metastasis.SIGNIFICANCE: 14-3-3 sigma has been identified as a normal mammary epithelial cell marker frequently downregulated during neoplastic development. Consistent with its potential role as a tumor suppressor, we demonstrate that targeted disruption of 14-3-3 sigma in a number of epithelial tissues can profoundly impact both the initiation and metastatic phases of ErbB2-mediated tumor progression through modulation of a number of distinct signaling networks. Cancer Discovery; 2(1); 68-81. (C) 2011 AACR.