FOXM1 is a transcriptional target of ERalpha and has a critical role in breast cancer endocrine sensitivity and resistance.
FOXM1 is a transcriptional target of ERalpha and has a critical role in breast cancer endocrine sensitivity and resistance.
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DOI：
10.1038/onc.2010.47
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发表时间：
2010-05-20
期刊：
影响因子：
8
通讯作者：
Lam, E. W-F
中科院分区：
文献类型：
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作者：
Millour, J.;Constantinidou, D.;Stavropoulou, A. V.;Wilson, M. S. C.;Myatt, S. S.;Kwok, J. M-M;Sivanandan, K.;Coombes, R. C.;Medema, R. H.;Hartman, J.;Lykkesfeldt, A. E.;Lam, E. W-F
本研究探讨雌激素受体α(ER-α)对FOXM1表达的调节及其在激素治疗和内分泌抵抗中的作用。在乳腺癌细胞系中，FOXM1蛋白和mRNA的表达受雌激素、三苯氧胺(OHT)和氟维斯特(ICI182780；ICI)等ER配体的调节。RNAi耗尽MCF-7细胞内ERα下调FOXM1的表达。报告基因分析表明，ERα通过位于近端启动子区域的雌激素反应元件(ERE)激活FOXM1转录。通过迁移率漂移和α下拉实验和体内染色质免疫沉淀(ChIP)分析，证实了ER FXM1与FOXM1启动子的直接结合。我们的数据还显示，在OHT处理时，ERα将组蛋白脱乙酰酶(HDAC)招募到FOXM1启动子的ERE位点，这与组蛋白乙酰化和转录活性降低有关。重要的是，RNAi沉默FOXM1可消除雌激素诱导的MCF-7细胞增殖，并克服获得性三苯氧胺耐药。相反，异位表达FOXM1可阻断抗雌激素OHT介导的细胞周期停滞。OHT抑制FOXM1在内分泌敏感但不耐药的乳腺癌细胞中的表达。此外，对乳腺癌患者的定量逆转录聚合酶链式反应分析显示，ERα和FOXM1mRNA的表达呈显著正相关。综上所述，这些结果表明FOXM1是ERα和雌激素在乳腺癌细胞中有丝分裂功能的关键介质，也表明FOXM1的解除调控可能有助于抗雌激素不敏感。
In this study we investigated the regulation of FOXM1 expression by estrogen receptor α (ERα) and its role in hormonal therapy and endocrine resistance. FOXM1 protein and mRNA expression was regulated by ER-ligands, including estrogen, tamoxifen (OHT), and fulvestrant (ICI182780; ICI) in breast carcinoma cell lines. Depletion of ERα by RNA interference (RNAi) in MCF-7 cells down-regulated FOXM1 expression. Reporter gene assays demonstrated that ERα activates FOXM1 transcription through an estrogen-response element (ERE) located within the proximal promoter region. The direct binding of ERα to the FOXM1 promoter was confirmed in vitro by mobility shift and DNA pull-down assays and in vivo by chromatin immunoprecipitation (ChIP) analysis. Our data also revealed that upon OHT treatment ERα recruits histone deacetylases (HDACs) to the ERE site of the FOXM1 promoter, which is associated with a decrease in histone acetylation and transcription activity. Importantly, silencing of FOXM1 by RNAi abolished estrogen-induced MCF-7 cell proliferation and overcame acquired tamoxifen resistance. Conversely, ectopic expression of FOXM1 abrogated the cell cycle arrest mediated by the anti-estrogen OHT. OHT repressed FOXM1 expression in endocrine sensitive but not resistant breast carcinoma cell lines. Further, qRT-PCR analysis of breast cancer patient samples revealed there was a strong and significant positive correlation between ERα and FOXM1 mRNA expression. Collectively, these results demonstrate FOXM1 to be a key mediator of the mitogenic functions of ERα and estrogen in breast cancer cells, and also suggest that the deregulation of FOXM1 may contribute to anti-estrogen insensitivity.
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