Negative cross talk between NFAT1 and Stat5 signaling in breast cancer.
Negative cross talk between NFAT1 and Stat5 signaling in breast cancer.
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DOI：
10.1210/me.2011-1141
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发表时间：
2011-09
影响因子：
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通讯作者：
Jiamao Zheng;Feng Fang;Xianke Zeng;Terry R. Medler;A. Fiorillo;C. Clevenger
中科院分区：
文献类型：
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作者：
Jiamao Zheng;Feng Fang;Xianke Zeng;Terry R. Medler;A. Fiorillo;C. Clevenger
在乳腺癌进展过程中调节信号转导子和转录激活子 5 (Stat5) 活性的分子机制仍然难以捉摸。在这里，我们提供的证据表明，钙调神经磷酸酶/活化 T 细胞核因子 (NFAT) 通路负向调节 Stat5 的激活，在乳腺癌中反之亦然。 NFAT1 与乳腺癌细胞中的 Stat5 相互作用，它们的物理关联由 Stat5 的 DNA 结合和反式激活结构域介导。异位表达的 NFAT1 能够抑制 Stat5 依赖性功能，包括 Stat5 反式激活、Stat5 介导的下游靶基因表达的转录以及 Stat5a 与 Stat5 靶启动子的结合。相比之下，选择性 NFAT 抑制剂 VIVIT 的过度表达逆转了 NFAT1 介导的 Stat5 依赖性基因表达抑制，而通过 RNA 干扰沉默 NFAT1 则增强了催乳素诱导的 Stat5 介导的基因转录和乳腺癌细胞增殖。还观察到 Stat5 活性对 NFAT1 信号传导的相互抑制作用，这意味着这两个信号级联在乳腺癌中相互拮抗。重要的是，对匹配的乳腺癌进展组织微阵列的分析揭示了乳腺癌进展过程中 NFAT1 和 Stat5 (pY694) 水平之间的负相关。总而言之，这些研究强调了 NFAT1 和 Stat5 信号级联之间的一种新型负串扰，可能影响乳腺肿瘤的形成、生长和转移。
The molecular mechanisms that modulate the activity of the signal transducers and activators of transcription 5 (Stat5) during the progression of breast cancer remain elusive. Here, we present evidence that the calcineurin/nuclear factor of activated T cells (NFAT) pathway negatively regulates the activation of Stat5, and vice versa in breast cancer. NFAT1 interacts with Stat5 in breast cancer cells, and their physical association is mediated by the DNA binding and transactivation domains of Stat5. Ectopically expressed NFAT1 is capable of inhibiting Stat5-dependent functions, including Stat5 transactivation, Stat5-mediated transcription of the downstream target gene expression, and binding of Stat5a to the Stat5 target promoter. By contrast, overexpression of a selective NFAT inhibitor VIVIT reversed NFAT1-mediated suppression of Stat5-dependent gene expression, whereas silencing of NFAT1 through RNA interference enhanced prolactin-induced, Stat5-mediated gene transcription, and breast cancer cell proliferation. A reciprocal inhibitory effect of Stat5 activity on NFAT1 signaling was also observed, implying these two signaling cascades antagonize each other in breast cancer. Importantly, analysis of a matched breast cancer progression tissue microarray revealed a negative correlation between levels of NFAT1 and Stat5 (pY694) during the progression of breast cancer. Taken together, these studies highlight a novel negative cross talk between the NFAT1- and Stat5-signaling cascades that may affect breast tumor formation, growth, and metastasis.