Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 8; pp. 2730 - 2735
• Main Authors: Mendes-Pereira, Ana M., Sims, David, Dexter, Tim, Fenwick, Kerry, Assiotis, Ioannis, Kozarewa, Iwanka, Mitsopoulos, Costas, Hakas, Jarle, Zvelebil, Marketa, Lord, Christopher J., Ashworth, Alan
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 21.02.2012; National Acad Sciences
• Series: Breast Cancer Special Feature
• Subjects: Biological Sciences; Breast cancer; BREAST CANCER SPECIAL FEATURE; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Cell Line, Tumor; Chemotherapy; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Drug Screening Assays, Antitumor; Estrogens; Female; Gene silencing; Genes; Genes, Neoplasm - genetics; Genetic screening; Genetic Testing - methods; Genome, Human - genetics; Genomics; Health outcomes; Humans; K-Ras protein; Libraries; Mortality; Relapse; Reproducibility of Results; RNA Interference - drug effects; RNA-mediated interference; Sequencing; Signal Transduction - drug effects; Small interfering RNA; Tamoxifen; Tamoxifen - pharmacology; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1018872108

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, INGS, 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.