The ligand status of the aromatic hydrocarbon receptor modulates transcriptional activation of BRCA-1 promoter by estrogen
The ligand status of the aromatic hydrocarbon receptor modulates transcriptional activation of BRCA-1 promoter by estrogen
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DOI：
10.1158/0008-5472.can-05-1619
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发表时间：
2006-02-15
期刊：
影响因子：
11.2
通讯作者：
Romagnolo, DF
中科院分区：
文献类型：
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作者：
Hockings, JK;Thorne, PA;Romagnolo, DF
在散发性乳腺癌中，BRCA-1基因在没有突变的情况下表达下调。这表明BRCA-1表达的破坏可能有助于乳腺肿瘤的发生。在工业污染、烟草烟雾和熟食中发现的环境污染物包括苯并(a)芘[B(a)P]和2,3,7,8-四氯二苯并-对二恶英（TCDD），它们已被证明具有内分泌干扰物和肿瘤促进剂的作用。在之前的研究中，我们证实了雌激素（E2）通过激活蛋白-1/雌激素受体- α (ER - α)复合物向近端BRCA-1启动子的募集来诱导BRCA-1转录。在这里，我们报道了E2激活BRCA-1转录需要未配体芳香烃受体（AhR）占据BRCA-1启动子。E2对BRCA-1转录的刺激作用被(a)与AhR拮抗剂3′-甲氧基-4′-硝基黄酮共处理抵消；(b)缺乏AhR蛋白结合域的ER α在ER α阴性HeLa细胞中的瞬时表达；(c)位于ER α结合区上游的两个一致的异种生物响应元件（XRE, 5-GCGTG-3’）的突变。这些结果表明，未配体AhR和配体ER α之间的物理相互作用在e2依赖性的BRCA-1转录激活中起积极作用。相反，我们发现AhR配体B(a)P和TCDD可以消除e2诱导的BRCA-1启动子活性。TCDD的抑制作用与配体AhR和HDAC1的招募增加，p300、SRC-1的占用减少以及XREs侧BRCA-1启动子区域H4乙酰化减少相似。我们认为AhR的配体状态通过雌激素调节BRCA-1启动子的激活。
In sporadic breast cancers, BRCA-1 expression is down-regulated in the absence of mutations in the BRCA-1 gene. This suggests that disruption of BRCA-1 expression may contribute to the onset of mammary tumors. Environmental contaminants found in industrial pollution, tobacco smoke, and cooked foods include benzo(a)pyrene [B(a)P] and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which have been shown to act as endocrine disruptors and tumor promoters. In previous studies, we documented that estrogen (E2) induced BRCA-1 transcription through the recruitment of an activator protein-1/estrogen receptor-alpha (ER alpha) complex to the proxima BRCA-1 promoter. Here, we report that activation of BRCA-1 transcription by E2 requires occupancy of the BRCA-1 promoter by the unliganded aromatic hydrocarbon receptor (AhR). The stimulatory effects of E2 on BRCA-1 transcription are counteracted by (a) cotreatment with the AhR antagonist 3'-methoxy-4'-nitroflavone; (b) transient expression in ER alpha-negative HeLa cells of ER alpha lacking the protein-binding domain for the AhR; and (c) mutation of two consensus xenobiotic-responsive elements (XRE, 5-GCGTG-3') located upstream of the ER alpha-binding region. These results suggest that the physical interaction between the unliganded AhR and the liganded ER alpha plays a positive role in E2-dependent activation of BRCA-1 transcription. Conversely, we show that the AhR ligands B(a)P and TCDD abrogate E2-induced BRCA-1 promoter activity. The repressive effects of TCDD are paralleled by increased recruitment of the liganded AhR and HDAC1, reduced occupancy by p300, SRC-1, and diminished acetylation of H4 at the BRCA-1 promoter region flanking the XREs. We propose that the ligand status of the AhR modulates activation of the BRCA-1 promoter by estrogen.