The transcription factor snail mediates epithelial to mesenchymal transitions by repression of estrogen receptor-α

被引:142
作者
Dhasarathy, Archana [1 ]
Kajita, Masahiro [1 ]
Wade, Paul A. [1 ]
机构
[1] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA
关键词
D O I
10.1210/me.2007-0293
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The estrogen receptor (ER)-alpha (ESR1) is a key regulatory molecule in mammary epithelial cell development. Loss of ER-alpha in breast cancer is correlated with poor prognosis, increased recurrence after treatment, and an elevated incidence of metastasis. A proposed molecular pathway by which ER-alpha acts to constrain invasive growth in breast cancer cells involves direct, ER-alpha-dependent expression of metastasis-associated protein 3, a cell-type-specific component of the Mi-2/NuRD chromatin remodeling complex. MTA3 in turn represses expression of Snail, a transcription factor linked to epithelial to mesenchymal transition and cancer metastasis. To elucidate its role(s) in epithelial to mesenchymal transition (EMT), we expressed Snail in the noninvasive, ER-alpha-positive MCF-7 cell line. Snail expression led to decreased cell-cell adhesion and increased cell invasiveness. Furthermore, we observed loss of ER-alpha expression at both the RNA and protein level that was accompanied by direct interaction of Snail with regulatory DNA sequences at the ESR1 locus. A consequence of loss of ER-alpha function in this system was the increased abundance of key components of the TGF-beta signaling pathway. Thus, cross-talk among ER-alpha, Snail, and the TGF-beta pathway appears to control critical phenotypic properties of breast cancer cells.
引用
收藏
页码:2907 / 2918
页数:12
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