Estrogen-related receptor alpha expression and function is associated with the transcriptional coregulator AIB1 in breast carcinoma.
Estrogen-related receptor alpha expression and function is associated with the transcriptional coregulator AIB1 in breast carcinoma.
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雌激素相关受体 α 的表达和功能与乳腺癌中的转录共调节因子 AIB1 相关。
作者：
S. Heck;J. Rom;V. Thewes;N. Becker;B. Blume;H. Sinn;U. Deuschle;C. Sohn;A. Schneeweiss;P. Lichter
最近报道了雌激素相关受体α（ERRα）作为乳腺癌不良临床结果的预后标志物的重要性。 ERRα 等核受体的转录活性取决于共调节蛋白。因此，我们比较了相同原发性乳腺肿瘤样本 (n = 48) 中不同受体、共调节因子和靶基因在 RNA 和蛋白质水平上的表达。我们发现 ERRalpha 和 AIB1（在乳腺癌-1 中扩增）的转录物之间存在正相关性，AIB1 是一种在乳腺癌中过度表达的共激活因子，与抗激素治疗的耐药性相关。这些数据在蛋白质水平上得到了证实，研究了独立的患者集合（n = 257）。雌激素调节基因 pS2 的表达仅在肿瘤中与 ERRα 相关，而肿瘤中雌激素受体 (ERα) 表达较低或不表达。在ERα高表达肿瘤中，没有观察到ERRα和pS2的相关性。荧光共振能量转移、哺乳动物双杂交和内源蛋白共免疫沉淀测定表明，AIB1 与 ERRalpha 直接相互作用。如功能报告基因测定所示，它增强 ERα 阴性乳腺癌细胞系中的 ERRα 转录活性。用反向激动剂阻断 ERRalpha 可消除 AIB1 的相互作用和共激活。将两种蛋白招募到 ERRalpha 靶基因启动子进一步支持了它们相互作用的重要性。我们的研究结果确定 AIB1 是乳腺癌中 ERRα 功能相关的辅助因子。 ERRalpha/AIB1 复合物可以以不依赖于激素的方式控制雌二醇调节基因。因此，ERRα 可能是治疗内分泌耐药肿瘤的一个有益靶点。
The significance of the estrogen-related receptor alpha (ERRalpha) as prognostic marker for poor clinical outcome in breast carcinoma has recently been reported. Transcriptional activity of nuclear receptors such as ERRalpha depends on coregulatory proteins. Thus, we compared the expression of different receptors, coregulators, and target genes on RNA and protein level in identical primary breast tumor samples (n = 48). We found a positive correlation between the transcripts of ERRalpha and AIB1 (amplified in breast cancer-1), a coactivator overexpressed in breast cancers and associated with resistance to antihormone treatment. These data were confirmed on protein level, studying an independent patient collection (n = 257). Expression of the estrogen-regulated gene pS2 was associated with ERRalpha only in tumors, where estrogen receptor (ERalpha) expression was low or absent. In ERalpha high expressing tumors, no correlation of ERRalpha and pS2 was observed. AIB1 interacts directly with ERRalpha as shown by fluorescence-resonance energy transfer, mammalian two-hybrid, and coimmunoprecipitation assays with endogenous proteins. It enhances ERRalpha transcriptional activity in ERalpha-negative breast cancer cell lines as shown in functional reporter gene assays. Blocking ERRalpha with an inverse agonist abolished interaction and coactivation by AIB1. Recruitment of both proteins to ERRalpha target gene promoters further supports the significance of their interaction. Our findings identify AIB1 as functionally relevant cofactor for ERRalpha in breast carcinoma. ERRalpha/AIB1 complexes may control estradiol-regulated genes in a hormone-independent manner. Accordingly, ERRalpha might be a rewarding target for treatment of endocrine-resistant tumors.
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影响因子：
4.8
作者：
Liu, DX;Zhang, ZP;Teng, CT
通讯作者：
Teng, CT
DOI：
10.1093/jnci/95.5.353
发表时间：
2003-03-05
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Osborne, CK;Bardou, V;Schiff, R
通讯作者：
Schiff, R
影响因子：
5.3
作者：
Zou, Yuhua;Niu, Wenze;Zhang, Chun-Li
通讯作者：
Zhang, Chun-Li
影响因子：
4.4
作者：
Jackson, A;Panayiotidis, P;Foroni, L
通讯作者：
Foroni, L
影响因子：
50.3
作者：
Torres-Arzayus, MI;de Mora, JF;Brown, M
通讯作者：
Brown, M