ELF5 modulates the estrogen receptor cistrome in breast cancer.,PLOS Genetics

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ELF5 modulates the estrogen receptor cistrome in breast cancer.
PLOS Genetics ( IF 4.0 ) Pub Date : 2020-01-02 , DOI: 10.1371/journal.pgen.1008531
Catherine L Piggin _{1,

2} , Daniel L Roden _{1,

2} , Andrew M K Law _{1,

2} , Mark P Molloy ₃ , Christoph Krisp ₃ , Alexander Swarbrick _{1,

2} , Matthew J Naylor _{1,

2,

4} , Maria Kalyuga _{1,

2} , Warren Kaplan _{1,

2} , Samantha R Oakes _{1,

2} , David Gallego-Ortega _{1,

2} , Susan J Clark _{1,

2} , Jason S Carroll ₅ , Nenad Bartonicek _{1,

2} , Christopher J Ormandy _{1,

2}

Affiliation

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.

中文翻译：

ELF5 调节乳腺癌中的雌激素受体顺反组。

乳腺癌治疗失败的一半原因是对内分泌治疗的获得性耐药。最近的研究结果表明 ETS 转录因子 ELF5 的表达增加是雌激素作用的潜在调节剂和内分泌抵抗的驱动因素，在这里我们首次深入了解 ELF5 调节雌激素敏感性的机制。使用染色质免疫沉淀测序，我们发现 ELF5 结合在超级增强子、增强子和启动子处与 FOXA1 和 ER 重叠，并且当升高时，导致 FOXA1 和 ER 与基因组的新区域结合，其模式将改变复制到 ER/ FOXA1顺反子引起内分泌治疗获得性耐药。 RNA测序表明，这些变化改变了雌激素驱动的基因表达模式、ER转录复合体成员的表达以及已知参与驱动内分泌抵抗获得的6个基因的表达。使用内源蛋白的快速免疫沉淀质谱和邻近连接测定，我们发现 ELF5 与 ER 转录复合物的成员（例如 DNA-PKcs）发生物理相互作用。我们发现了 2 例内分泌抵抗性脑转移瘤，与匹配的原发肿瘤相比，ELF5 水平大大增加，并且 ELF5 基因表达模式丰富。因此，ELF5 通过调节 ER/FOXA1 顺反子、与其相互作用以及调节 ER 转录复合体成员的表达来改变 ER 驱动的基因表达，从而提供 ELF5 驱动内分泌抵抗的多种机制。

更新日期：2020-02-18

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