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Nature解析乳腺癌耐药机理:雌激素受体改变与基因结合位置

2012/01/07 来源:新华网
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导读
雌激素受体与DNA链条上的基因相互结合的位置遵循常规,所以常规药物有效。雌激素受体改变了“工作路线”,转移到其他位置上与基因结合,所以患者对常规药物产生耐药性。

乳腺检查

英国的一项新研究显示,部分乳腺癌患者对常用的治疗药物表现出耐药性,其原因是体内的雌激素受体改变了“工作路线”。

雌激素受体是一种能与基因结合的物质。在许多乳腺癌患者体内,就是因为该受体影响了基因的功能,从而引发致癌连锁反应。现在常用的他莫昔芬等乳腺癌治疗药物,就是通过阻断雌激素受体对基因的作用而发挥效果。但在不少患者身上,这种药物的效果并不理想。

英国剑桥大学等机构的研究人员在英国《自然》杂志网络版上报告说,他们对比了药物疗效良好和出现耐药性的患者,发现在前一类患者体内,雌激素受体与DNA链条上的基因相互结合的位置遵循常规,所以常规药物有效。而在后一类患者体内,雌激素受体改变了“工作路线”,转移到其他位置上与基因结合,所以患者对常规药物产生耐药性。

此次研究还发现,在雌激素受体的新“工作路线”中,一种名为FOXA1的蛋白质发挥了重要的中介作用。研究人员卡洛斯·卡尔达斯说,约三分之一的乳腺癌患者都对他莫昔芬等药物有耐药性或是在治疗一段时间后复发,如果能有针对性地抑制FOXA1蛋白质的功能,也许可以改善这部分乳腺癌患者的状况。


参考文献

Differential oestrogen receptor binding is associated with clinical outcome in breast cancer

Caryn S. Ross-Innes,  Rory Stark,  Andrew E. Teschendorff,  Kelly A. Holmes,  H. Raza Ali,  Mark J. Dunning,  Gordon D. Brown,  Ondrej Gojis,  Ian O. Ellis,  Andrew R. Green,  Simak Ali,  Suet-Feung Chin,  Carlo Palmieri,  Carlos Caldas  & Jason S. Carroll

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. Here we 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 outcomes and in distant ER-positive metastases. We find that drug-resistant cancers still recruit ER to the chromatin, 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 ER regulatory regions associated with poor clinical outcome observed in primary tumours reveal gene signatures that predict clinical outcome in ER-positive 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 timescale. The parallel redistribution of ER and FOXA1 binding events 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.

文献链接:http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10730.html

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