title: Functional characterization of EMSY gene amplification in human cancers.
abstract: The 11q13-q14 locus is frequently amplified in human cancers, with a complex structure harbouring multiple potential oncogenic drivers. The EMSY gene has been proposed as a driver of the third core of the 11q13-q14 amplicon. This gene encodes a protein reported to be a BRCA2-binding partner, which when over-expressed would lead to impairment of BRCA2 functions and could constitute a mechanism for BRCA2 inactivation in non-hereditary breast and ovarian cancers. We hypothesized that if EMSY amplification abrogates BRCA2 functions, cells harbouring this aberration would be unable to elicit competent homologous recombination DNA repair and, therefore, may have increased sensitivity to genotoxic therapies and potent PARP inhibitors. Microarray-based comparative genomic hybridization of cell lines from distinct tumour sites, including breast, ovary, pancreas, oesophagus, lung and the oral cavity, led to the identification of 10 cell lines with EMSY amplification and 18 without. EMSY amplification was shown to correlate with EMSY mRNA levels, although not all cell lines harbouring EMSY amplification displayed EMSY mRNA or protein over-expression. RNA interference-mediated silencing of EMSY did not lead to a reduction in cell viability in tumour models harbouring EMSY amplification. Cell lines with and without EMSY amplification displayed a similar ability to elicit RAD51 foci in response to DNA damaging agents, and similar sensitivity to cisplatin and olaparib. Taken together, this suggests that EMSY is unlikely to be a driver of the 11q13-q14 amplicon and does not have a dominant role in modulating the response to agents targeting cells with defective homologous recombination.
authors: Molecular Pathology Team, Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
authors: Paul M
authors: PM
authors: Wilkerson
authors: Konstantin J
authors: KJ
authors: Dedes
authors: Daniel
authors: D
authors: Wetterskog
authors: Alan
authors: A
authors: Mackay
authors: Maryou B
authors: MB
authors: Lambros
authors: Marthe
authors: M
authors: Mansour
authors: Jessica
authors: J
authors: Frankum
authors: Christopher J
authors: CJ
authors: Lord
authors: Rachael
authors: R
authors: Natrajan
authors: Alan
authors: A
authors: Ashworth
authors: Jorge S
authors: JS
authors: Reis-Filho
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D055028:Comparative Genomic Hybridization; D004260:DNA Repair / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020868:Gene Silencing; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051135:Rad51 Recombinase / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; C480344:EMSY protein, human; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D002945:Cisplatin; C531550:olaparib