Laboratory of Molecular Medicine and Genomics, Faculty of Medicine and Surgery, University of Salerno, via S. Allende 1, 84081 Baronissi, Salerno, Italy.
Horm Cancer. 2012 Jun;3(3):65-78. doi: 10.1007/s12672-012-0102-1.
Oestrogen receptor alpha (ERα) is a ligand-dependent transcription factor that mediates oestrogen effects in hormone-responsive cells. Following oestrogenic activation, ERα directly regulates the transcription of target genes via DNA binding. MicroRNAs (miRNAs) represent a class of small noncoding RNAs that function as negative regulators of protein-coding gene expression. They are found aberrantly expressed or mutated in cancer, suggesting their crucial role as either oncogenes or tumour suppressor genes. Here, we analysed changes in miRNA expression in response to oestrogen in hormone-responsive breast cancer MCF-7 and ZR-75.1 cells by microarray-mediated expression profiling. This led to the identification of 172 miRNAs up- or down-regulated by ERα in response to 17β-oestradiol, of which 52 are similarly regulated by the hormone in the two cell models investigated. To identify mechanisms by which ERα exerts its effects on oestrogen-responsive miRNA genes, the oestrogen-dependent miRNA expression profiles were integrated with global in vivo ERα binding site mapping in the genome by ChIP-Seq. In addition, data from miRNA and messenger RNA (mRNA) expression profiles obtained under identical experimental conditions were compared to identify relevant miRNA target transcripts. Results show that miRNAs modulated by ERα represent a novel genomic pathway to impact oestrogen-dependent processes that affect hormone-responsive breast cancer cell behaviour. MiRNome analysis in tumour tissues from breast cancer patients confirmed a strong association between expression of these small RNAs and clinical outcome of the disease, although this appears to involve only marginally the oestrogen-regulated miRNAs identified in this study.
雌激素受体 α（ERα）是一种配体依赖性转录因子，可介导激素反应细胞中的雌激素作用。雌激素激活后，ERα 通过 DNA 结合直接调节靶基因的转录。微小 RNA（miRNA）是一类小的非编码 RNA，作为蛋白质编码基因表达的负调控因子。它们在癌症中表现出异常表达或突变，表明它们作为癌基因或肿瘤抑制基因的关键作用。在这里，我们通过微阵列介导的表达谱分析，分析了激素反应性乳腺癌 MCF-7 和 ZR-75.1 细胞中雌激素对 miRNA 表达的影响。这导致了 172 个 miRNA 的鉴定，这些 miRNA 受 ERα 调节，对 17β-雌二醇有反应，其中 52 个在两个研究的细胞模型中受激素类似调节。为了确定 ERα 对雌激素反应性 miRNA 基因施加影响的机制，将雌激素依赖性 miRNA 表达谱与通过 ChIP-Seq 在基因组中进行的体内 ERα 结合位点映射的全局图谱进行了整合。此外，还比较了在相同实验条件下获得的 miRNA 和信使 RNA（mRNA）表达谱的数据，以鉴定相关的 miRNA 靶转录物。结果表明，受 ERα 调节的 miRNA 代表了一种影响雌激素依赖性过程的新型基因组途径，这些过程影响激素反应性乳腺癌细胞的行为。对乳腺癌患者肿瘤组织中的 MiRNome 分析证实，这些小 RNA 的表达与疾病的临床结果之间存在很强的关联，尽管这似乎仅涉及本研究中鉴定的雌激素调节的 miRNA 中的一小部分。
