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首页> 外文期刊>Oncogene >Expression of estrogen receptor |[beta]| isoforms in normal breast epithelial cells and breast cancer: regulation by methylation
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Expression of estrogen receptor |[beta]| isoforms in normal breast epithelial cells and breast cancer: regulation by methylation

机译：雌激素受体|β|的表达正常乳腺上皮细胞和乳腺癌中的亚型：通过甲基化调控

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Two novel estrogen receptor (ER) mRNA isoforms that diverge in their 5'-untranslated regions, ER mRNA (0K-1) and ER mRNA (0N-1), have recently been identified. This indicates that transcription of the human ER gene occurs from at least two different promoters, named promoter 0K and promoter 0N. The aim of this study was to investigate the expression of ER isoforms in primary cultures of normal breast epithelial cells, a panel of breast cancer cell lines and in normal breast and breast cancer tissues; and to examine whether methylation of the two ER promoters is involved in regulation of ER gene expression. Using quantitative real-time PCR techniques, we found that ER mRNA levels were significantly lower in breast cancer cell lines than in primary cultures of normal breast epithelial cells. Bisulfite genomic sequencing analysis revealed that two promoters of the ER gene exhibit distinct methylation patterns. Promoter 0N was unmethylated in normal breast epithelial cells, but extensively methylated in breast cancer cell lines. In contrast, promoter 0K was unmethylated in both normal and malignant breast epithelial cells. We demonstrated a significant correlation between promoter 0N hypermethylation and loss of ER mRNA expression in breast cancer cell lines. Treatment of breast cancer cells with demethylating agent effectively reactivated the expression of ER mRNA. The observations from the cell lines were also reflected in primary breast cancer tumors. Thus, expression of ER mRNA in breast tumors was found to be inversely associated with the degree of methylation of promoter 0N. Our results suggest that a decreased level of ER mRNA may be associated with breast tumorigenesis, and that DNA methylation is an important mechanism for ER gene silencing in breast cancer.
机译：最近发现了两个在其5'非翻译区发生分歧的新型雌激素受体（ER）mRNA同工型，即ER mRNA（0K-1）和ER mRNA（0N-1）。这表明人ER基因的转录发生于至少两个不同的启动子，分别称为启动子0K和启动子0N。这项研究的目的是研究ER同工型在正常乳腺上皮细胞，一组乳腺癌细胞系以及正常乳腺和乳腺癌组织中的表达。并检查两个ER启动子的甲基化是否参与ER基因表达的调控。使用定量实时PCR技术，我们发现乳腺癌细胞系中的ER mRNA水平显着低于正常乳腺癌上皮细胞的原代培养。亚硫酸氢盐基因组测序分析表明，ER基因的两个启动子表现出不同的甲基化模式。启动子0N在正常的乳腺上皮细胞中未甲基化，但是在乳腺癌细胞系中被广泛甲基化。相反，启动子0K在正常和恶性乳腺上皮细胞中均未甲基化。我们证明了在乳腺癌细胞系中启动子0N超甲基化与ER mRNA表达缺失之间存在显着相关性。用去甲基化剂处理乳腺癌细胞可有效地重新激活ER mRNA的表达。来自细胞系的观察结果也反映在原发性乳腺癌肿瘤中。因此，发现ER mRNA在乳腺肿瘤中的表达与启动子0N的甲基化程度呈负相关。我们的结果表明，ER mRNA的降低水平可能与乳腺癌的发生有关，并且DNA甲基化是乳腺癌中ER基因沉默的重要机制。

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