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首页> 外文期刊>PLoS Genetics >ELF5 modulates the estrogen receptor cistrome in breast cancer
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ELF5 modulates the estrogen receptor cistrome in breast cancer

机译：ELF5在乳腺癌中调节雌激素受体车腔

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Acquired resistance to endocrine therapy is responsible for half of the therapeutic failures in the treatment of breast cancer. Recent findings have implicated increased expression of the ETS transcription factor ELF5 as a potential modulator of estrogen action and driver of endocrine resistance, and here we provide the first insight into the mechanisms by which ELF5 modulates estrogen sensitivity. Using chromatin immunoprecipitation sequencing we found that ELF5 binding overlapped with FOXA1 and ER at super enhancers, enhancers and promoters, and when elevated, caused FOXA1 and ER to bind to new regions of the genome, in a pattern that replicated the alterations to the ER/FOXA1 cistrome caused by the acquisition of resistance to endocrine therapy. RNA sequencing demonstrated that these changes altered estrogen-driven patterns of gene expression, the expression of ER transcription-complex members, and 6 genes known to be involved in driving the acquisition of endocrine resistance. Using rapid immunoprecipitation mass spectrometry of endogenous proteins, and proximity ligation assays, we found that ELF5 interacted physically with members of the ER transcription complex, such as DNA-PKcs. We found 2 cases of endocrine-resistant brain metastases where ELF5 levels were greatly increased and ELF5 patterns of gene expression were enriched, compared to the matched primary tumour. Thus ELF5 alters ER-driven gene expression by modulating the ER/FOXA1 cistrome, by interacting with it, and by modulating the expression of members of the ER transcriptional complex, providing multiple mechanisms by which ELF5 can drive endocrine resistance.
机译：获得对内分泌治疗的抗性负责治疗乳腺癌的一半治疗失败。最近的发现具有含有对ETS转录因子ELF5作为雌激素抗性的潜在调节剂的潜在调节剂的增加，并且在这里，我们提供了对ELF5调节雌激素敏感性的机制的第一洞察力。使用染色质免疫沉淀序列，我们发现在超级增强剂，增强剂和启动子的福索氮和ER重叠的ELF5结合，并且当升高时，导致Foxa1和ER结合到基因组的新区域，以将改变复制到ER / Foxa1车辆由收购对内分泌治疗的抵抗力引起的。 RNA测序证明，这些变化改变了基因表达的雌激素驱动模式，ER转录复合构件的表达和已知6个基因涉及驱动内分泌抗性的抗性。利用内源蛋白的快速免疫沉淀质谱和邻近结扎测定，我们发现ELF5物理地与ER转录复合物的成员相互作用，例如DNA-PKC。我们发现2例内分泌抗性脑转移，与匹配的原发性肿瘤相比，富含ELF5水平的ELF5水平富集了基因表达的ELF5模式。因此，通过与其相互作用，通过调节ER / FOXA1分叉组，并通过调节ER转录复合物的成员的表达，提供多种机制，通过调节ER / FOXA1传感器，提供多种机制，从而改变ER驱动的基因表达。

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