Prince Henry's Institute, Monash Medical Centre, 246 Clayton Road, Clayton, Melbourne, Vic 3168, Australia.
Steroids. 2011 Jul;76(8):741-4. doi: 10.1016/j.steroids.2011.02.024. Epub 2011 Mar 8.
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 PGE₂ 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 12-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 shLRH-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.
在绝经后乳腺癌中，肿瘤相关脂肪基质细胞中观察到的芳香酶表达增加是通过启动子 II（PII）转录的上调介导的。诸如 PGE₂ 等从乳腺癌中分泌的因子诱导 PII 表达。孤儿核受体 LRH-1/NR5A2 是这种效应的关键下游转录介导因子之一。本研究的目的是确定 LRH-1 是否可以直接结合 PII，以及抑制 LRH-1 表达是否可以抑制人脂肪基质成纤维细胞中的芳香酶表达。染色质免疫沉淀实验表明，在基础条件下以及用 forskolin 和佛波醇 12-肉豆蔻酸 13-乙酸酯（PMA）处理时，内源性 LRH-1 占据 PII。为了评估 LRH-1 敲低对 FSK/PMA 介导的 PII 表达的影响，用靶向 LRH-1 的 shRNA（shLRH-1）转染细胞，并用 forskolin 和 PMA 处理。与对照相比，shLRH-1 转染细胞在基础和处理条件下的 LRH-1、PII 和总芳香酶 mRNA 转录物均减少。这项研究的结果支持了这样一种假设，即抑制 LRH-1 可能在绝经后乳腺癌中芳香酶表达的组织特异性调节中具有潜在益处。
