Increases in estrogen receptor-α concentration in breast cancer cells promote serine 118/104/106-independent AF-1 transactivation and growth in the absence of estrogen
Increases in estrogen receptor-α concentration in breast cancer cells promote serine 118/104/106-independent AF-1 transactivation and growth in the absence of estrogen
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DOI：
10.1096/fj.03-0038com
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发表时间：
2004-01-01
期刊：
影响因子：
4.8
通讯作者：
Alarid, ET
中科院分区：
文献类型：
--
作者：
Fowler, AM;Solodin, N;Alarid, ET
乳腺癌的一个常见表型是雌激素受体-α（ER+）细胞群的扩增和ER α蛋白的不适当升高，后者使患者的预后比受体水平较低的患者更差。在MCF-7细胞系中开发了四环素诱导的ER α过表达模型，以评估响应ER α蛋白升高的内源性基因激活和生长的诱导。ER α水平升高导致在激素不存在的情况下异常启动子占用和基因激活，这与配体和AF-2功能无关。这种增加的受体活性需要氨基末端A/B结构域，并且不被他莫昔芬抑制，他莫昔芬支持AF-1功能的增强，但不依赖于丝氨酸-104，106和118磷酸化。配体非依赖性转录伴随着在激素刺激的情况下生长的增加。结果表明，乳腺癌细胞中ER α水平升高可导致受体转录功能的激活，其方式与涉及配体结合或生长因子诱导的磷酸化的经典机制不同。此外，他们还描述了一种潜在的机制，即无论配体状态如何，ER α浓度的增加都可以通过增强ER α功能来提供增殖优势。
A common phenotype in breast cancer is the expansion of the estrogen receptor-alpha (ER+) cell population and an inappropriate elevation of ERalpha protein, the latter predisposing patients for a poorer prognosis than those with lower levels of the receptor. A tetracycline-inducible ERalpha overexpression model was developed in the MCF-7 cell line to assess induction of endogenous gene activation and growth in response to elevations in ERalpha protein. Heightened levels of ERalpha resulted in aberrant promoter occupancy and gene activation in the absence of hormone, which was independent of ligand and AF-2 function. This increased receptor activity required the amino-terminal A/B domain and was not inhibited by tamoxifen, which supports an enhancement of AF-1 function, yet was independent of serine-104, 106, and 118 phosphorylation. Ligand-independent transcription was accompanied by an increase in growth in the absence of hormonal stimulation. The results suggest that elevated levels of ERalpha in breast cancer cells can result in activation of receptor transcriptional function in a manner distinct from classical mechanisms that involve ligand binding or growth factor-induced phosphorylation. Further, they describe a potential mechanism whereby increases in ERalpha concentration may provide a proliferative advantage by augmenting ERalpha function regardless of ligand status.