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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen
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Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen

机译：全基因组功能筛选可鉴定影响他莫昔芬敏感性的基因汇编

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摘要

Therapies that target estrogen signaling have made a very considerable contribution to reducing mortality from breast cancer. However, resistance to tamoxifen remains a major clinical problem. Here we have used a genome-wide functional profiling approach to identify multiple genes that confer resistance or sensitivity to tamoxifen. Combining whole-genome shRNA screening with massively parallel sequencing, we have profiled the impact of more than 56,670 RNA interference reagents targeting 16,487 genes on the cellular response to tamoxifen. This screen, along with subsequent validation experiments, identifies a compendium of genes whose silencing causes tamoxifen resistance (including BAP1, CLPP, GPRCSD, NAE1, NF1, NIPBL. NSD1, RAD21, RARG, SMC3, and UBA3) and also a set of genes whose silencing causes sensitivity to this endocrine agent (C10orf72, C15orf55/NUT, EDF1, ING5, KRAS, NOC3L, PPP1R15B. RRAS2, TMPRSS2, and TPM4). Multiple individual genes, including NF1, a regulator of RAS signaling, also correlate with clinical outcome after tamoxifen treatment.
机译：靶向雌激素信号传导的疗法对降低乳腺癌的死亡率做出了巨大贡献。然而，对他莫昔芬的抗药性仍然是主要的临床问题。在这里，我们使用了全基因组功能分析方法来鉴定赋予他莫昔芬耐药性或敏感性的多个基因。将全基因组shRNA筛选与大规模并行测序相结合，我们已经分析了针对16,487个基因的超过56,670种RNA干扰试剂对他莫昔芬细胞反应的影响。此屏幕以及随后的验证实验，鉴定了其沉默导致他莫昔芬抗性的基因概要（包括BAP1，CLPP，GPRCSD，NAE1，NF1，NIPBL，NSD1，RAD21，RARG，SMC3和UBA3），以及一组基因其沉默会导致对此内分泌剂（C10orf72，C15orf55 / NUT，EDF1，ING5，KRAS，NOC3L，PPP1R15B，RRAS2，TMPRSS2和TPM4）敏感。他莫昔芬治疗后的多个个体基因，包括NF1，RAS信号的调节剂，也与临床结果相关。

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    Ana M. Mendes-Pereira; David Sims; Tim Dexter; Kerry Fenwick; loannis Assiotis; Iwanka Kozarewa; Costas Mitsopoulos; Jarle Hakas; Marketa Zvelebil; Christopher J. Lord; Alan Ash worth;

  • 作者单位

    Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, Institute of Cancer Research, London SW3 6JB, United Kingdom;

    Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, Institute of Cancer Research, London SW3 6JB, United Kingdom;

    Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, Institute of Cancer Research, London SW3 6JB, United Kingdom;

    Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, Institute of Cancer Research, London SW3 6JB, United Kingdom;

    Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, Institute of Cancer Research, London SW3 6JB, United Kingdom;

    Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, Institute of Cancer Research, London SW3 6JB, United Kingdom;

    Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, Institute of Cancer Research, London SW3 6JB, United Kingdom;

    Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, Institute of Cancer Research, London SW3 6JB, United Kingdom;

    Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, Institute of Cancer Research, London SW3 6JB, United Kingdom;

    Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, Institute of Cancer Research, London SW3 6JB, United Kingdom;

    Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, Institute of Cancer Research, London SW3 6JB, United Kingdom;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    genetics; endocrine therapy; RNA interference screening; next generation sequencing;

    机译：遗传学内分泌疗法RNA干扰筛选;下一代测序;

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