Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells
Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells
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DOI：
10.1093/carcin/bci339
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发表时间：
2006-08-01
期刊：
影响因子：
4.7
通讯作者：
Naegeli, Hanspeter
中科院分区：
文献类型：
--
作者：
Buterin, Tonko;Koch, Caroline;Naegeli, Hanspeter
雌激素受体在容纳广泛的配体结构中显示出高水平的混杂性，但与不同激动剂复合的受体构象改变的功能后果是高度有争议的。为了确定不同雌激素激动剂诱导的反式激活能力的变化，我们评估了天然或合成的异种雌激素与内源性激素17 β-雌二醇相比引起的全球转录谱。人MCF 7和T47 D癌细胞，代表最常用的模型系统，在乳腺中的致瘤反应，同步激素饥饿48小时。随后，用等浓度的所选异种雌激素或17 β-雌二醇进行24小时暴露。信使RNA的分析进行高密度的寡核苷酸微阵列，显示33000人转录本的序列，共产生181个基因产物，调节后雌激素刺激。令人惊讶的是，染料木黄酮（一种植物雌激素）、双酚A和多氯联苯同源物54（两种合成的异种雌激素）通过调节相同范围的人类基因产生了高度一致的基因组指纹。此外，响应于异种雌激素观察到的单调的基因组签名与生理浓度的17 β-雌二醇诱导的转录效应相同。这种惊人的功能趋同表明，转录机制在很大程度上是不敏感的雌激素受体激动剂的特定结构。这种会聚转录程序的发生强化了以下假设：多种天然或人为来源的外源性雌激素污染物可能与内源性激素一起作用，以诱导靶组织中的累加效应。
Estrogen receptors display high levels of promiscuity in accommodating a wide range of ligand structures, but the functional consequence of changing receptor conformations in complex with distinct agonists is highly controversial. To determine variations in the transactivation capacity induced by different estrogenic agonists, we assessed global transcriptional profiles elicited by natural or synthetic xenoestrogens in comparison with the endogenous hormone 17 beta-estradiol. Human MCF7 and T47D carcinoma cells, representing the most frequently used model systems for tumorigenic responses in the mammary gland, were synchronized by hormone starvation during 48 h. Subsequently, a 24 h exposure was carried out with equipotent concentrations of the selected xenoestrogens or 17 beta-estradiol. Analysis of messenger RNA was performed on high-density oligonucleotide microarrays that display the sequences of 33000 human transcripts, yielding a total of 181 gene products that are regulated upon estrogenic stimulation. Surprisingly, genistein (a phytoestrogen), bisphenol-A and polychlorinated biphenyl congener 54 (two synthetic xenoestrogens) produced highly congruent genomic fingerprints by regulating the same range of human genes. Also, the monotonous genomic signature observed in response to xenoestrogens is identical to the transcriptional effects induced by physiological concentrations of 17 beta-estradiol. This striking functional convergence indicates that the transcription machinery is largely insensitive to the particular structure of estrogen receptor agonists. The occurrence of such converging transcriptional programs reinforces the hypothesis that multiple xenoestrogenic contaminants, of natural or anthropogenic origin, may act in conjunction with the endogenous hormone to induce additive effects in target tissues.