Differential oestrogen receptor binding is associated with clinical outcome in breast cancer.
Differential oestrogen receptor binding is associated with clinical outcome in breast cancer.
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鉴定雌激素受体结合与乳腺癌的临床结局有关。
DOI：
10.1038/nature10730
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发表时间：
2012-01-04
期刊：
影响因子：
64.8
通讯作者：
Carroll, Jason S.
中科院分区：
文献类型：
--
作者：
Ross-Innes, Caryn S.;Stark, Rory;Teschendorff, Andrew E.;Holmes, Kelly A.;Ali, H. Raza;Dunning, Mark J.;Brown, Gordon D.;Gojis, Ondrej;Ellis, Ian O.;Green, Andrew R.;Ali, Simak;Chin, Suet-Feung;Palmieri, Carlo;Caldas, Carlos;Carroll, Jason S.
雌激素受体-α（ER）是大多数乳腺癌中的定义和驱动转录因子，其靶基因决定细胞生长和内分泌反应，但对ER功能的基因组理解仅限于模型系统。我们现在通过染色质免疫沉淀，然后进行高通量测序（ChIP-seq），在具有不同临床结果的原发性乳腺癌患者和远处ER阳性（ER+）转移患者中绘制全基因组ER结合事件。我们发现耐药癌症仍然具有ER染色质占据，但ER结合是一个动态过程，在可能复发的患者的肿瘤中获得独特的ER结合区域。在原发性肿瘤中观察到的获得性、不良结果ER调控区揭示了仅预测ER+疾病临床结果的基因特征。我们发现，在预后不良患者的肿瘤中观察到的差异ER结合程序不是由于选择了罕见的细胞亚群，而是由于FoxA 1介导的ER结合在快速时间尺度上的重编程。ER和FoxA 1顺式调节元件在耐药细胞环境中的平行再分布得到转移样品中ER和FoxA 1的组织学共表达的支持。通过在原发性肿瘤材料中建立转录因子图谱，我们发现ER结合能力具有可塑性，顺式调节元件的不同组合与不同的临床结果相关。
Oestrogen receptor-α (ER) is the defining and driving transcription factor in the majority of breast cancers and its target genes dictate cell growth and endocrine response, yet genomic understanding of ER function has been restricted to model systems. We now map genome-wide ER binding events, by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), in primary breast cancers from patients with different clinical outcome and in distant ER positive (ER+) metastases. We find that drug resistant cancers still have ER-chromatin occupancy, but that ER binding is a dynamic process, with the acquisition of unique ER binding regions in tumours from patients that are likely to relapse. The acquired, poor outcome ER regulatory regions observed in primary tumours reveal gene signatures that predict clinical outcome in ER+ disease exclusively. We find that the differential ER binding programme observed in tumours from patients with poor outcome is not due to the selection of a rare subpopulation of cells, but is due to the FoxA1-mediated reprogramming of ER binding on a rapid time scale. The parallel redistribution of ER and FoxA1 cis-regulatory elements in drug resistant cellular contexts is supported by histological co-expression of ER and FoxA1 in metastatic samples. By establishing transcription factor mapping in primary tumour material, we show that there is plasticity in ER binding capacity, with distinct combinations of cis-regulatory elements linked with the different clinical outcomes.
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影响因子：
4.5
作者：
Lin CY;Vega VB;Thomsen JS;Zhang T;Kong SL;Xie M;Chiu KP;Lipovich L;Barnett DH;Stossi F;Yeo A;George J;Kuznetsov VA;Lee YK;Charn TH;Palanisamy N;Miller LD;Cheung E;Katzenellenbogen BS;Ruan Y;Bourque G;Wei CL;Liu ET
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通讯作者：
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