Tissue-specific regulation of aromatase promoter II by the orphan nuclear receptor LRH-1 in breast adipose stromal fibroblasts
Tissue-specific regulation of aromatase promoter II by the orphan nuclear receptor LRH-1 in breast adipose stromal fibroblasts
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DOI：
10.1016/j.steroids.2011.02.024
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发表时间：
2011-07-01
期刊：
影响因子：
2.7
通讯作者：
Clyne, Colin D.
中科院分区：
文献类型：
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作者：
Chand, Ashwini L.;Herridge, Kerrie A.;Clyne, Colin D.
在绝经后乳腺癌中，肿瘤相关脂肪基质细胞中芳香化酶表达的增加是通过上调启动子II(PII)转录来实现的。乳腺癌分泌的PGE(2)等因子可诱导PII的表达。孤儿核受体LRH-1/NR5A2是这一效应的关键下游转录介质之一。本研究的目的是确定LRH-1是否可以直接与PII结合，以及抑制LRH-1的表达是否可以抑制人脂肪基质成纤维细胞中芳香化酶的表达。染色质免疫沉淀显示内源性LRH-1在基础条件下和福司可林和佛波酯(PMA)处理的PII上占据。为了评估LRH-1基因敲除对FSK/PMA介导的PII表达的影响，将针对LRH-1的shRNA(shLRH-1)导入细胞，并用Forsklin和PMA处理。在基础和处理条件下，5hLRH-1转基因细胞中LRH-1、PII和总芳香酶mRNA的转录水平均低于对照组。这项研究的结果支持这样的假设，即抑制LRH-1可能在绝经后乳腺癌芳香酶表达的组织特异性调节中具有潜在的益处。(C)2011 Elsevier Inc.保留所有权利。
In postmenopausal breast cancers, the increase in aromatase expression observed in tumour associated adipose stromal cells is mediated via the upregulation of promoter II (PII) transcription. Factors such as PGE(2) which are secreted from breast carcinomas induce PII expression. The orphan nuclear receptor LRH-1 /NR5A2 is one of the critical downstream transcriptional mediators of this effect. The aim of the current study was to determine whether LRH-1 could bind directly to PII and whether the suppression of LRH-1 expression could inhibit aromatase expression in human adipose stromal fibroblasts. Chromatin immunoprecipitation demonstrated endogenous LRH-1 occupancy on PII under basal conditions and with treatment with forskolin and phorbol 1 2-myristate 13-acetate (PMA). To assess the impact of LRH-1 knockdown on FSK/PMA mediated PII expression, cells were transfected with shRNA targeted against LRH-1 (shLRH-1) and treated with forskolin and PMA. A decrease in LRH-1, PII and total aromatase mRNA transcripts was observed in 5hLRH-1 transfected cells compared to controls under basal and treatment conditions. The results of this study support the hypothesis that suppression of LRH-1 may potentially be beneficial in the tissue specific regulation of aromatase expression in post menopausal breast cancer. (C) 2011 Elsevier Inc. All rights reserved.