Caveolin-1 upregulation mediates suppression of primary breast tumor growth and brain metastases by stat3 inhibition.
Caveolin-1 upregulation mediates suppression of primary breast tumor growth and brain metastases by stat3 inhibition.
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DOI：
10.1158/0008-5472.can-10-4249
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发表时间：
2011-07-15
期刊：
影响因子：
11.2
通讯作者：
Huang S
中科院分区：
文献类型：
--
作者：
Chiu WT;Lee HT;Huang FJ;Aldape KD;Yao J;Steeg PS;Chou CY;Lu Z;Xie K;Huang S
Stat 3激活被认为是乳腺癌脑转移的重要驱动因素，但Stat 3在这一过程中的关键靶点尚未完全确定。在这项研究中，我们确定了脂筏组织蛋白Caveolin-1（Cav-1）作为一个关键的遗传目标的Stat 3在这个过程中。在人类乳腺癌中，我们发现活化的Stat 3与脑转移瘤中Cav-1相对于原发性肿瘤的衰减相关。Cav-1启动子的活性和基因表达增加了过表达的活化形式的Stat 3，但减少了衰减的Stat 3的活性或表达。我们确定了假定的Stat 3结合元件的Cav-1启动子，并证明了直接抑制Cav-1转录Stat 3。反过来，我们证明了增加或减少Cav-1表达的策略足以减弱或促进乳腺癌细胞的侵袭。此外，Cav-1表达的增加表型模仿了Stat 3激活在阻断原发性肿瘤生长和消除脑转移形成中的作用。总的来说，我们的研究结果提供了临床和机制证据，证明Cav-1是Stat 3抑制乳腺癌细胞侵袭和转移的关键靶点。
Stat3 activation has been implicated as an important driver of brain metastasis in breast cancer, but the critical targets of Stat3 in this process are yet to be fully defined. In this study, we identified the lipid raft organizing protein Caveolin-1 (Cav-1) as a critical genetic target of Stat3 in this process. In human breast cancers, we found that activated Stat3 correlated with attenuation of Cav-1 in brain metastases relative to primary tumors. Cav-1 promoter activity and gene expression was increased by overexpressing an activated form of Stat3, but decreased by attenuation of Stat3 activity or expression. We identified putative Stat3-binding elements in the Cav-1 promoter and demonstrated a direct repression of Cav-1 transcription by Stat3. Reciprocally, we demonstrated that strategies to increase or decrease Cav-1 expression were sufficient to attenuate or promote breast cancer cell invasion. Further, increased expression of Cav-1 phenocopied the effects of Stat3 activation in blocking primary tumor growth and abrogating formation of brain metastases. Collectively, our findings provide clinical and mechanistic evidence that Cav-1 is a critical target for suppression by Stat3 in driving invasion and metastasis of breast cancer cells.