BACKGROUND Non-ER nuclear receptor activity can alter estrogen receptor (ER) chromatin association and resultant ER-mediated transcription. Consistent with GR modulation of ER activity, high tumor glucocorticoid receptor (GR) expression correlates with improved relapse-free survival in ER+ breast cancer (BC) patients. METHODS In vitro cell proliferation assays were used to assess ER-mediated BC cell proliferation following GR modulation. ER chromatin association following ER/GR co-liganding was measured using global ChIP sequencing and directed ChIP analysis of proliferative gene enhancers. RESULTS We found that GR liganding with either a pure agonist or a selective GR modulator (SGRM) slowed estradiol (E2)-mediated proliferation in ER+ BC models. SGRMs that antagonized transcription of GR-unique genes both promoted GR chromatin association and inhibited ER chromatin localization at common DNA enhancer sites. Gene expression analysis revealed that ER and GR co-activation decreased proliferative gene activation (compared to ER activation alone), specifically reducing CCND1, CDK2, and CDK6 gene expression. We also found that ligand-dependent GR occupancy of common ER-bound enhancer regions suppressed both wild-type and mutant ER chromatin association and decreased corresponding gene expression. In vivo, treatment with structurally diverse SGRMs also reduced MCF-7 Y537S ER-expressing BC xenograft growth. CONCLUSION These studies demonstrate that liganded GR can suppress ER chromatin occupancy at shared ER-regulated enhancers, including CCND1 (Cyclin D1), regardless of whether the ligand is a classic GR agonist or antagonist. Resulting GR-mediated suppression of ER+ BC proliferative gene expression and cell division suggests that SGRMs could decrease ER-driven gene expression.

中文翻译：

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糖皮质激素受体调节降低了ER阳性乳腺癌细胞的增殖，并抑制了野生型和突变型ER染色质的缔合。

背景技术非ER核受体活性可以改变雌激素受体（ER）染色质缔合和由此产生的ER介导的转录。与ER活性的GR调节相一致，高肿瘤糖皮质激素受体（GR）的表达与ER +乳腺癌（BC）患者的无复发生存期改善有关。方法采用体外细胞增殖试验评估GR调节后ER介导的BC细胞增殖。ER / GR共配体后的ER染色质缔合使用整体ChIP测序和增殖基因增强子的直接ChIP分析进行测量。结果我们发现，用纯激动剂或选择性GR调节剂（SGRM）进行GR配位可减缓ER + BC模型中雌二醇（E2）介导的增殖。拮抗GR独特基因转录的SGRM既促进GR染色质缔合，又抑制ER染色质在常见DNA增强子位点的定位。基因表达分析表明，ER和GR共激活可降低增殖性基因激活（与单独的ER激活相比），特别是降低CCND1，CDK2和CDK6基因表达。我们还发现常见的ER结合的增强子区域依赖配体的GR占用抑制了野生型和突变体ER染色质缔合，并降低了相应的基因表达。在体内，用结构多样的SGRMs处理还减少了表达MCF-7 Y537S ER的BC异种移植物的生长。结论这些研究表明，配体GR可以抑制在共享的ER调节增强子（包括CCND1（Cyclin D1））上的ER染色质占据。无论配体是经典的GR激动剂还是拮抗剂。结果导致GR介导的ER + BC增殖基因表达和细胞分裂的抑制表明SGRMs可以降低ER驱动的基因表达。