Constitutive activation of STAT3 in breast cancer cells: A review.
Constitutive activation of STAT3 in breast cancer cells: A review.
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DOI：
10.1002/ijc.29923
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发表时间：
2016-06-01
影响因子：
6.4
通讯作者：
Resat H
中科院分区：
文献类型：
--
作者：
Banerjee K;Resat H
信号转导子和转录激活子3（STAT 3）在许多癌症类型中被组成性激活，包括超过40%的乳腺癌。与STAT 3作为正常细胞中的潜在转录因子的严格调控相反，其在乳腺癌肿瘤发生中的信号传导是多方面的。通过IL 6/JAK/STAT 3途径的信号传导由IL 6家族的细胞因子（即，IL-6、IL-11）与其受体的相互作用与乳腺癌的发展有关。具有内在激酶活性的受体如EGFR和VEGFR直接或间接诱导各种乳腺癌类型中的STAT 3活化。异常的STAT 3信号通过下游靶基因表达的失调促进乳腺肿瘤的进展，这些靶基因控制增殖（Bcl-2、Bcl-xL、Survivin、Cyclin D1、c-Myc、Mcl-1）、血管生成（Hif 1 α、VEGF）和上皮-间质转化（波形蛋白、TWIST、MMP-9、MMP-7）。因此，STAT 3调节的多种模式使其成为多种信号传导过程的中心连接点。在过去，针对乳腺癌中STAT 3激活的广泛努力没有取得显着的成功，因为STAT 3信号传导的高度互连性质导致STAT 3靶向分子疗法的途径鉴定缺乏选择性，或者因为其在肿瘤发生中的作用可能不像想象的那样重要。本文综述了STAT 3在乳腺癌中的作用，通过巩固其在多个层面上的作用的知识，提供了一个全方位的STAT 3参与乳腺癌：其不同的受体信号通路的差异调节，其下游靶基因，其转录活性的修改，其共调节转录因子。
Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in numerous cancer types, including more than 40% of breast cancers. In contrast to tight regulation of STAT3 as a latent transcription factor in normal cells, its signaling in breast cancer oncogenesis is multifaceted. Signaling through the IL6/JAK/STAT3 pathway initiated by the binding of IL6 family of cytokines (i.e., IL-6, IL-11) to their receptors have been implicated in breast cancer development. Receptors with intrinsic kinase activity such as EGFR and VEGFR directly or indirectly induce STAT3 activation in various breast cancer types. Aberrant STAT3 signaling promotes breast tumor progression through deregulation of the expression of downstream target genes which control proliferation (Bcl-2, Bcl-xL, Survivin, Cyclin D1, c-Myc, Mcl-1), angiogenesis (Hif1α, VEGF), and epithelial-mesenchymal transition (Vimentin, TWIST, MMP-9, MMP-7). These multiple modes of STAT3 regulation therefore make it a central linking point for a multitude of signaling processes. Extensive efforts to target STAT3 activation in breast cancer had no remarkable success in the past because the highly-interconnected nature of STAT3 signaling introduces lack of selectivity in pathway identification for STAT3 targeted molecular therapies or because its role in tumorigenesis may not be as critical as it was thought. This review provides a full spectrum of STAT3’s involvement in breast cancer by consolidating the knowledge about its role in breast cancer development at multiple levels: its differential regulation by different receptor signaling pathways, its downstream target genes, and modification of its transcriptional activity by its co-regulatory transcription factors.