Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, Institute of Cancer Research, London SW3 6JB, United Kingdom.
Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2730-5. doi: 10.1073/pnas.1018872108. Epub 2011 Apr 11.
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, GPRC5D, 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.
针对雌激素信号的治疗方法在降低乳腺癌死亡率方面做出了非常重要的贡献。然而，对他莫昔芬的耐药性仍然是一个主要的临床问题。在这里，我们使用全基因组功能谱分析方法来鉴定出多个赋予他莫昔芬耐药性或敏感性的基因。通过全基因组 shRNA 筛选与大规模平行测序相结合，我们对超过 56670 种针对 16487 个基因的 RNA 干扰试剂对他莫昔芬的细胞反应的影响进行了分析。该筛选以及随后的验证实验确定了一组基因的综合，其沉默导致他莫昔芬耐药（包括 BAP1、CLPP、GPRC5D、NAE1、NF1、NIPBL、NSD1、RAD21、RARG、SMC3 和 UBA3），以及一组基因的沉默导致对这种内分泌药物的敏感性（C10orf72、C15orf55/NUT、EDF1、ING5、KRAS、NOC3L、PPP1R15B、RRAS2、TMPRSS2 和 TPM4）。多个单个基因，包括 NF1，一种 RAS 信号的调节剂，也与他莫昔芬治疗后的临床结果相关。
