Runx1 stabilizes the mammary epithelial cell phenotype and prevents epithelial to mesenchymal transition.
Runx1 stabilizes the mammary epithelial cell phenotype and prevents epithelial to mesenchymal transition.
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DOI：
10.18632/oncotarget.15381
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发表时间：
2017-03-14
期刊：
影响因子：
--
通讯作者：
Stein GS
中科院分区：
文献类型：
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作者：
Hong D;Messier TL;Tye CE;Dobson JR;Fritz AJ;Sikora KR;Browne G;Stein JL;Lian JB;Stein GS
Runx 1是造血分化所必需的转录因子，Runx 1突变是白血病的原因。Runx 1在大多数腺体的正常上皮中高度表达，最近已与实体瘤相关。值得注意的是，Runx 1在乳腺中的功能以及它如何参与乳腺癌的发生和发展仍不清楚。在这里，我们展示了Runx 1损失在正常乳腺上皮细胞和乳腺癌细胞的后果。我们首先观察到Runx 1在致瘤性和转移性乳腺癌细胞中减少。我们还观察到Runx 1表达的损失后，诱导上皮-间充质转化（EMT）的MCF 10A（正常样）细胞。此外，MCF 10A细胞中Runx 1的缺失导致细胞形状的显著变化，导致间充质细胞形态。通过重新表达Runx 1，可以在乳腺癌细胞中恢复上皮表型。对乳腺肿瘤和患者数据的分析显示，Runx 1低表达与预后不良和生存率降低相关。我们探讨了Runx 1在维持上皮表型中的功能机制，发现Runx 1直接调节E-cadherin;并作为下游转录因子介导TGFβ信号转导。我们还通过生长因子耗竭细胞的整体基因表达谱观察到，EMT的诱导和Runx 1的缺失与TGFβ和WNT途径的激活相关。因此，这些发现已经确定了Runx 1在维持正常上皮形态和预防EMT方面的新功能，并表明Runx 1水平可能是肿瘤进展的预后指标。
Runx1 is a well characterized transcription factor essential for hematopoietic differentiation and Runx1 mutations are the cause of leukemias. Runx1 is highly expressed in normal epithelium of most glands and recently has been associated with solid tumors. Notably, the function of Runx1 in the mammary gland and how it is involved in initiation and progression of breast cancer is still unclear. Here we demonstrate the consequences of Runx1 loss in normal mammary epithelial and breast cancer cells. We first observed that Runx1 is decreased in tumorigenic and metastatic breast cancer cells. We also observed loss of Runx1 expression upon induction of epithelial-mesenchymal transition (EMT) in MCF10A (normal-like) cells. Furthermore depletion of Runx1 in MCF10A cells resulted in striking changes in cell shape, leading to mesenchymal cell morphology. The epithelial phenotype could be restored in breast cancer cells by re-expressing Runx1. Analyses of breast tumors and patient data revealed that low Runx1 expression is associated with poor prognosis and decreased survival. We addressed mechanisms for the function of Runx1 in maintaining the epithelial phenotype and find Runx1 directly regulates E-cadherin; and serves as a downstream transcription factor mediating TGFβ signaling. We also observed through global gene expression profiling of growth factor depleted cells that induction of EMT and loss of Runx1 is associated with activation of TGFβ and WNT pathways. Thus these findings have identified a novel function for Runx1 in sustaining normal epithelial morphology and preventing EMT and suggest Runx1 levels could be a prognostic indicator of tumor progression.