MTA1 promotes STAT3 transcription and pulmonary metastasis in breast cancer.
MTA1 promotes STAT3 transcription and pulmonary metastasis in breast cancer.
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DOI：
10.1158/0008-5472.can-12-3998
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发表时间：
2013-06-15
期刊：
影响因子：
11.2
通讯作者：
Kumar R
中科院分区：
文献类型：
--
作者：
Pakala SB;Rayala SK;Wang RA;Ohshiro K;Mudvari P;Reddy SD;Zheng Y;Pires R;Casimiro S;Pillai MR;Costa L;Kumar R
在人类癌症中，促转移性染色质修饰蛋白MTA1的过表达有助于肿瘤的侵袭性，但内源性MTA1在癌症中的作用尚未被探索。在这里，我们报道了MTA1的选择性基因缺失对乳腺癌肺转移的生理相关自发性小鼠模型的影响。我们发现MTA1是乳房到肺转移的强制性修饰因子，对原发肿瘤的形成没有影响。潜在的机制涉及通过MTA1/ STAT3/ Pol II共激活因子复合物的作用，MTA1依赖性地刺激STAT3转录，进而影响包括Twist1在内的STAT3靶基因的表达和功能。因此，我们在公开的乳腺癌数据集中记录了MTA1和STAT3水平之间的正相关。总之，我们的研究结果揭示了MTA1生理水平在支持乳腺癌肺转移中的重要调节作用。
Overexpression of the pro-metastatic chromatin modifier protein MTA1 in human cancer contributes to tumor aggressiveness, but the role of endogenous MTA1 in cancer has not been explored. Here we report the effects of selective genetic depletion of MTA1 in a physiologically relevant spontaneous mouse model of breast cancer pulmonary metastasis. We found that MTA1 acts as a mandatory modifier of breast-to-lung metastasis without effects on primary tumor formation. The underlying mechanism involved MTA1-dependent stimulation of STAT3 transcription through action on the MTA1/ STAT3/ Pol II coactivator complex, and in turn, on the expression and functions of STAT3 target genes including Twist1. Accordingly, we documented a positive correlation between levels of MTA1 and STAT3 in publicly available breast cancer data sets. Together, our findings reveal an essential modifying role of the physiologic level of MTA1 in supporting pulmonary metastasis of breast cancer.