Mendes-Pereira, AM and Sims, D and Dexter, T and Fenwick, K and Assiotis, I and Kozarewa, I and Mitsopoulos, C and Hakas, J and Zvelebil, M and Lord, CJ and Ashworth, A (2012) Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen. Proc Natl Acad Sci U S A , 109 (8) 2730 - 2735. 10.1073/pnas.1018872108.
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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.
|Title:||Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen.|
|Additional information:||PMCID: PMC3286962|
|Keywords:||Breast Neoplasms, Cell Line, Tumor, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Female, Genes, Neoplasm, Genetic Testing, Genome, Human, Humans, RNA Interference, Reproducibility of Results, Signal Transduction, Tamoxifen|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Structural and Molecular Biology|
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