The transcription factor snail mediates epithelial to mesenchymal transitions by repression of estrogen receptor-α
The transcription factor snail mediates epithelial to mesenchymal transitions by repression of estrogen receptor-α
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DOI：
10.1210/me.2007-0293
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发表时间：
2007-12-01
影响因子：
--
通讯作者：
Wade, Paul A.
中科院分区：
文献类型：
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作者：
Dhasarathy, Archana;Kajita, Masahiro;Wade, Paul A.
雌激素受体(ER)-α(ESR1)是乳腺上皮细胞发育的关键调控分子。乳腺癌中ER-α的缺失与预后不良、治疗后复发增加和转移率升高有关。已提出的ER-α抑制乳腺癌细胞侵袭生长的分子途径涉及转移相关蛋白3的直接、依赖于ER的表达，转移相关蛋白3是Mi-2/NuRD染色质重塑复合体的一种细胞类型特异性成分。MTA3反过来抑制Snail的表达，Snail是一种与上皮向间充质转化和癌症转移有关的转录因子。为了阐明Snail在上皮向间充质转化中的作用(S)，我们在ERα阳性的非侵袭性MCF-7细胞系中表达Snail。Snail基因的表达降低了细胞间的黏附力，增加了细胞的侵袭力。此外，我们观察到ER-α在RNA和蛋白质水平上的丢失，伴随着Snail与ESR1基因上的调控DNA序列的直接相互作用。在这个系统中，ER-α功能丧失的一个后果是转化生长因子-β信号通路的关键成分增加。因此，ER-α、Snail和转化生长因子-β途径之间的相互作用似乎控制着乳腺癌细胞的关键表型特性。
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.