title: Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen.
abstract: 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.
authors.affiliation: Breakthrough Breast Cancer Research Centre,  Division of Breast Cancer Research, Institute of Cancer Research, London SW3 6JB,  United Kingdom.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Mendes-Pereira
authors.forename: David
authors.initials: D
authors.lastname: Sims
authors.forename: Tim
authors.initials: T
authors.lastname: Dexter
authors.forename: Kerry
authors.initials: K
authors.lastname: Fenwick
authors.forename: Ioannis
authors.initials: I
authors.lastname: Assiotis
authors.forename: Iwanka
authors.initials: I
authors.lastname: Kozarewa
authors.forename: Costas
authors.initials: C
authors.lastname: Mitsopoulos
authors.forename: Jarle
authors.initials: J
authors.lastname: Hakas
authors.forename: Marketa
authors.initials: M
authors.lastname: Zvelebil
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D005260:Female; D052138:Genes, Neoplasm / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods*; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D034622:RNA Interference / Q000187:drug effects*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D013629:Tamoxifen