O'Donnell Amanda J M, Macleod Kenneth G, Burns David J, Smyth John F, Langdon Simon P
Cancer Research UK Centre, University of Edinburgh.
Endocr Relat Cancer. 2005 Dec;12(4):851-66. doi: 10.1677/erc.1.01039.
Estrogens play a significant role in the development, growth, invasion and metastasis of ovarian tumors. The transcriptional program regulated by 17beta-estradiol (E(2)) in human ovarian cancer cell lines was analyzed using cDNA microarrays containing 1200 cancer-related genes. Twenty-eight transcripts had at least a threefold change in expression in E(2)-treated PEO1 ovarian carcinoma cells compared with controls. These differences were confirmed by real-time quantitative PCR and shown to be dependent upon the expression of functional estrogen receptor-alpha (ERalpha). Consistent with this, these gene expression changes were blocked by the anti-estrogen tamoxifen. The use of ERalpha- and ERbeta-specific ligands allowed molecular dissection of the E(2) response and showed that ERalpha activation was responsible for the observed changes in gene expression, whereas ERbeta played no significant role. Inhibition of de novo protein synthesis by cycloheximide was used to distinguish between primary and secondary target genes regulated by E(2). Actinomycin D was used to show that changes in gene expression levels induced by E(2) were a result of changes in transcription and not due to changes in mRNA stability. The results presented here demonstrate that estrogen-driven growth of epithelial ovarian carcinoma is mediated by activation of ERalpha-mediated, and not ERbeta-mediated, transcription.
雌激素在卵巢肿瘤的发生、生长、侵袭和转移中发挥着重要作用。使用包含1200个癌症相关基因的cDNA微阵列分析了17β-雌二醇（E₂）在人卵巢癌细胞系中调控的转录程序。与对照相比，在E₂处理的PEO1卵巢癌细胞中，28个转录本的表达至少有三倍的变化。这些差异通过实时定量PCR得到证实，并显示依赖于功能性雌激素受体α（ERα）的表达。与此一致的是，这些基因表达变化被抗雌激素他莫昔芬阻断。使用ERα和ERβ特异性配体能够对E₂反应进行分子剖析，结果表明ERα的激活是观察到的基因表达变化的原因，而ERβ没有发挥显著作用。使用放线菌酮抑制从头蛋白质合成来区分由E₂调控的初级和次级靶基因。使用放线菌素D表明，E₂诱导的基因表达水平变化是转录变化的结果，而不是由于mRNA稳定性的变化。此处呈现的结果表明，雌激素驱动的上皮性卵巢癌生长是由ERα介导而非ERβ介导的转录激活所介导的。
