近日,，英國劍橋大學等機構(gòu)的研究人員在英國Nature雜志網(wǎng)絡版上發(fā)表報告"Differential oestrogen receptor binding is associated with clinical outcome in breast cancer"說，部分乳腺癌患者對常用的治療藥物表現(xiàn)出耐藥性,，其原因是體內(nèi)的雌激素受體改變了“工作路線”,。
雌激素受體是一種能與基因結(jié)合的物質(zhì)。在許多乳腺癌患者體內(nèi),，就是因為該受體影響了基因的功能,，從而引發(fā)致癌連鎖反應?，F(xiàn)在常用的他莫昔芬等乳腺癌治療藥物，就是通過阻斷雌激素受體對基因的作用而發(fā)揮效果,。但在不少患者身上,，這種藥物的效果并不理想。
研究人員對比了藥物療效良好和出現(xiàn)耐藥性的患者,，發(fā)現(xiàn)在前一類患者體內(nèi),，雌激素受體與DNA鏈條上的基因相互結(jié)合的位置遵循常規(guī)，所以常規(guī)藥物有效,。而在后一類患者體內(nèi),，雌激素受體改變了“工作路線”，轉(zhuǎn)移到其他位置上與基因結(jié)合,，所以患者對常規(guī)藥物產(chǎn)生耐藥性,。
此次研究還發(fā)現(xiàn)，在雌激素受體的新“工作路線”中,，一種名為FOXA1的蛋白質(zhì)發(fā)揮了重要的中介作用,。研究人員卡洛斯·卡爾達斯說，約三分之一的乳腺癌患者都對他莫昔芬等藥物有耐藥性或是在治療一段時間后復發(fā),，如果能有針對性地抑制FOXA1蛋白質(zhì)的功能,，也許可以改善這部分乳腺癌患者的狀況。（生物谷bioon.com）
doi:10.1038/nature10730
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PMID:
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.
