Estrogen signaling through estrogen receptor alpha (ER) plays a major role in endometrial cancer risk and progression, however, the molecular mechanisms underlying ER's regulatory role in endometrial cancer are poorly understood. In breast cancer cells, ER genomic binding is enabled by FOXA1 and GATA3, but the transcription factors that control ER genomic binding in endometrial cancer cells remain unknown. We previously identified ETV4 as a candidate factor controlling ER genomic binding in endometrial cancer cells, and here we explore the functional importance of ETV4. Homozygous deletion of ETV4, using CRISPR/Cas9, led to greatly reduced ER binding at the majority of loci normally bound by ER. Consistent with the dramatic loss of ER binding, the gene expression response to estradiol was dampened for most genes. ETV4 contributes to estrogen signaling in two distinct ways. ETV4 loss affects chromatin accessibility at some ER bound loci and impairs ER nuclear translocation. The diminished estrogen signaling upon ETV4 deletion led to decreased growth, particularly in 3D culture, where hollow organoids were formed and in vivo in the context of estrogen-dependent growth. These results show that ETV4 plays an important role in estrogen signaling in endometrial cancer cells. SIGNIFICANCE: ER is a key oncogene in endometrial cancer. This study uncovers ETV4 as an important factor in controlling the activity of ER and the growth of endometrial cancer cells. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/00/0/000/F1.large.jpg.

中文翻译：

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ETV4 对于子宫内膜癌细胞的雌激素信号传导和生长是必需的。


通过雌激素受体α (ER) 进行的雌激素信号传导在子宫内膜癌风险和进展中发挥着重要作用，然而，人们对 ER 在子宫内膜癌中调节作用的分子机制知之甚少。在乳腺癌细胞中，FOXA1 和 GATA3 能够实现 ER 基因组结合，但在子宫内膜癌细胞中控制 ER 基因组结合的转录因子仍然未知。我们之前将 ETV4 确定为控制子宫内膜癌细胞中 ER 基因组结合的候选因子，在这里我们探讨了 ETV4 的功能重要性。使用 CRISPR/Cas9 纯合删除 ETV4，导致大多数通常与 ER 结合的位点的 ER 结合大大减少。与 ER 结合的急剧丧失一致，大多数基因对雌二醇的基因表达反应受到抑制。 ETV4 以两种不同的方式促进雌激素信号传导。 ETV4 缺失会影响某些 ER 结合位点的染色质可及性，并损害 ER 核易位。 ETV4 缺失后雌激素信号减弱导致生长下降，特别是在 3D 培养中，其中形成中空类器官，并且在雌激素依赖性生长的体内。这些结果表明ETV4在子宫内膜癌细胞的雌激素信号传导中发挥重要作用。意义：ER 是子宫内膜癌的关键癌基因。这项研究发现 ETV4 是控制 ER 活性和子宫内膜癌细胞生长的重要因素。图解摘要：http://cancerres.aacrjournals.org/content/canres/00/0/000/F1.large.jpg。