Regulation of endogenous gene expression in human non-small cell lung cancer cells by estrogen receptor ligands
Regulation of endogenous gene expression in human non-small cell lung cancer cells by estrogen receptor ligands
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DOI：
10.1158/0008-5472.can-04-2694
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发表时间：
2005-02-15
期刊：
影响因子：
11.2
通讯作者：
Nichols, M
中科院分区：
文献类型：
--
作者：
Hershberger, PA;Vasquez, AC;Nichols, M
雌激素受体（ER）激动剂和拮抗剂在非小细胞肺癌（NSCLC）细胞中引起不同的反应。为了确定这种反应是如何产生的，通过免疫印迹法评估了ER α、ER β和ER辅调节因子在人肺成纤维细胞和人NSCLC细胞系中的表达。NSCLC细胞中的配体依赖性雌激素反应可能是通过ER β和p160共激活因子GRIP 1/TIF 2产生的，因为检测到这些蛋白质的表达，但未检测到全长ER α或p160共激活因子SRC-1。ER β和GRIP 1/TIF 2在体外以配体依赖性方式相互作用，因此可能在NSCLC细胞中形成功能性转录复合物。此外，使用基因微阵列探索ER配体调节NSCLC细胞中基因表达的能力。在用ER激动剂17-β-雌二醇（E2）、纯ER拮抗剂ICI 182，780（氟维司群，芙仕得）或表皮生长因子（作为替代生长刺激的阳性对照）处理后，检查了表达谱。在201 T和273 T NSCLC细胞系中，E2与ICI 182，780对E-cadherin和分化抑制因子2的调节存在差异。表皮生长因子也刺激这些细胞的增殖，但对E-cadherin和分化抑制因子2的表达没有影响，表明它们是ER信号传导的特异性靶点。这些数据表明，NSCLC细胞通过改变内源性基因表达对雌激素/抗雌激素产生反应，并支持一种模型，其中10182，780通过其破坏ER信号传导的能力降低NSCLC细胞的增殖。因此，ICI 182，780可能在NSCLC中具有治疗益处。
Estrogen receptor (ER) agonists and antagonists elicit distinct responses in non-small cell lung cancer (NSCLC) cells. To determine how such responses are generated, the expression of ERalpha, ERbeta, and ER coregulators in human lung fibroblasts and human NSCLC cell lines was evaluated by immunoblot. Ligand-dependent estrogenic responses in NSCLC cells are probably generated via ERbeta and the p160 coactivator GRIP1/TIF2, because expression of these proteins was detected, but not full-length ERalpha or the p160 coactivator SRC-1. ERbeta and GRIP1/TIF2 are shown to interact in vitro in a ligand-dependent manner and thus may form functional transcription complexes in NSCLC cells. Furthermore, the capacity of ER ligands to regulate gene expression in NSCLC cells was explored using gene miniarrays. Expression profiles were examined after treatment with ER agonist 17-beta-estradiol (E2), the pure ER antagonist ICI 182,780 (fulvestrant, Faslodex), or epidermal growth factor, which served as a positive control for an alternative growth stimulus. E-cadherin and inhibitor of differentiation 2 were differentially regulated by E2 versus ICI 182,780 in 201T and 273T NSCLC cell lines. Epidermal growth factor also stimulated proliferation of these cells but had no effect on expression of E-cadherin and inhibitor of differentiation 2, suggesting they are specific targets of ER signaling. These data show that NSCLC cells respond to estrogens/antiestrogens by altering endogenous gene expression and support a model in which 10 182,780 reduces proliferation of NSCLC cells via its ability to disrupt ER signaling. ICI 182,780 may therefore have therapeutic benefit in NSCLC.