GATA3 Transcription Factor Abrogates Smad4 Transcription Factor-mediated Fascin Overexpression, Invadopodium Formation, and Breast Cancer Cell Invasion
GATA3 Transcription Factor Abrogates Smad4 Transcription Factor-mediated Fascin Overexpression, Invadopodium Formation, and Breast Cancer Cell Invasion
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DOI：
10.1074/jbc.m113.506535
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发表时间：
2013-12-27
影响因子：
4.8
通讯作者：
Yang, Shengyu
中科院分区：
文献类型：
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作者：
Sun, Jianwei;He, Huifang;Yang, Shengyu
转化生长因子（TGF）是一种有效的和环境依赖性的肿瘤进展调节因子。TGF促进基底细胞样乳腺癌的肺转移（而非管腔样乳腺癌）。在这里，我们证明了fascin，一种促转移肌动蛋白捆绑蛋白，是基底样乳腺癌细胞中典型TGF-Smad 4信号通路的直接靶点。TGF和Smad 4通过直接结合到肌成束蛋白启动子上的Smad结合元件来诱导肌成束蛋白过表达。我们确定了GATA 3，一种对乳腺形态发生和管腔分化至关重要的转录因子，作为TGF-和Smad 4诱导的肌成束蛋白过表达的负调节因子。当在基底样乳腺癌细胞中异位表达时，加塔-3消除了TGF-和Smad 4介导的成束蛋白和其他TGF反应基因的过表达、侵袭足的形成、细胞迁移和侵袭，表明典型的TGF-Smad信号传导轴的抑制。从机制上讲，GATA 3通过消除Smad 4及其DNA结合元件之间的相互作用，可能通过GATA 3和Smad 3/4蛋白的N-末端之间的物理相互作用，消除了典型的TGF-Smad信号传导。我们的研究结果提供了TGF介导的细胞运动性和侵袭性在乳腺癌中的差异调节机制。
Transforming growth factor (TGF) is a potent and context-dependent regulator of tumor progression. TGF promotes the lung metastasis of basal-like (but not the luminal-like) breast cancer. Here, we demonstrated that fascin, a pro-metastasis actin bundling protein, was a direct target of the canonical TGF-Smad4 signaling pathway in basal-like breast cancer cells. TGF and Smad4 induced fascin overexpression by directly binding to a Smad binding element on the fascin promoter. We identified GATA3, a transcription factor crucial for mammary gland morphogenesis and luminal differentiation, as a negative regulator of TGF- and Smad4-induced fascin overexpression. When ectopically expressed in basal-like breast cancer cells, GATA-3 abrogated TGF- and Smad4-mediated overexpression of fascin and other TGF response genes, invadopodium formation, cell migration, and invasion, suggesting suppression of the canonical TGF-Smad signaling axis. Mechanistically, GATA3 abrogated the canonical TGF-Smad signaling by abolishing interactions between Smad4 and its DNA binding elements, potentially through physical interactions between the N-terminal of GATA3 and Smad3/4 proteins. Our findings provide mechanistic insight into how TGF-mediated cell motility and invasiveness are differentially regulated in breast cancer.