title: EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer.
abstract: The BRCA2 gene is mutated in familial breast and ovarian cancer, and its product is implicated in DNA repair and transcriptional regulation. Here we identify a protein, EMSY, which binds BRCA2 within a region (exon 3) deleted in cancer. EMSY is capable of silencing the activation potential of BRCA2 exon 3, associates with chromatin regulators HP1beta and BS69, and localizes to sites of repair following DNA damage. EMSY maps to chromosome 11q13.5, a region known to be involved in breast and ovarian cancer. We show that the EMSY gene is amplified almost exclusively in sporadic breast cancer (13%) and higher-grade ovarian cancer (17%). In addition, EMSY amplification is associated with worse survival, particularly in node-negative breast cancer, suggesting that it may be of prognostic value. The remarkable clinical overlap between sporadic EMSY amplification and familial BRCA2 deletion implicates a BRCA2 pathway in sporadic breast and ovarian cancer.
authors.affiliation: Cancer Research UK/Wellcome Trust Institute and Department of Pathology, Tennis Court Road, Cambridge CB2 1QR, United Kingdom. lh205@cus.cam.ac.uk
authors.forename: Luke
authors.initials: L
authors.lastname: Hughes-Davies
authors.forename: David
authors.initials: D
authors.lastname: Huntsman
authors.forename: Margarida
authors.initials: M
authors.lastname: Ruas
authors.forename: Francois
authors.initials: F
authors.lastname: Fuks
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Bye
authors.forename: Suet-Feung
authors.initials: SF
authors.lastname: Chin
authors.forename: Jonathon
authors.initials: J
authors.lastname: Milner
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Brown
authors.forename: Forrest
authors.initials: F
authors.lastname: Hsu
authors.forename: Blake
authors.initials: B
authors.lastname: Gilks
authors.forename: Torsten
authors.initials: T
authors.lastname: Nielsen
authors.forename: Michael
authors.initials: M
authors.lastname: Schulzer
authors.forename: Stephen
authors.initials: S
authors.lastname: Chia
authors.forename: Joseph
authors.initials: J
authors.lastname: Ragaz
authors.forename: Anthony
authors.initials: A
authors.lastname: Cahn
authors.forename: Lori
authors.initials: L
authors.lastname: Linger
authors.forename: Hilal
authors.initials: H
authors.lastname: Ozdag
authors.forename: Elena
authors.initials: E
authors.lastname: Cattaneo
authors.forename: E S
authors.initials: ES
authors.lastname: Jordanova
authors.forename: Edward
authors.initials: E
authors.lastname: Schuuring
authors.forename: David S
authors.initials: DS
authors.lastname: Yu
authors.forename: Ashok
authors.initials: A
authors.lastname: Venkitaraman
authors.forename: Bruce
authors.initials: B
authors.lastname: Ponder
authors.forename: Aidan
authors.initials: A
authors.lastname: Doherty
authors.forename: Samuel
authors.initials: S
authors.lastname: Aparicio
authors.forename: David
authors.initials: D
authors.lastname: Bentley
authors.forename: Charles
authors.initials: C
authors.lastname: Theillet
authors.forename: Chris P
authors.initials: CP
authors.lastname: Ponting
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.forename: Tony
authors.initials: T
authors.lastname: Kouzarides
mesh_terms: D024682:BRCA2 Protein / Q000172:deficiency / Q000235:genetics*; D001483:Base Sequence / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D018797:Cell Cycle Proteins; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D056970:Co-Repressor Proteins; D018076:DNA, Complementary / Q000032:analysis / Q000235:genetics; D004268:DNA-Binding Proteins; D005091:Exons / Q000235:genetics; D005260:Female; D005784:Gene Amplification / Q000235:genetics; D020868:Gene Silencing / Q000502:physiology; D005809:Genes, Regulator / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D010802:Phylogeny; D010940:Plant Proteins / Q000235:genetics; D011379:Prognosis; D017434:Protein Structure, Tertiary / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000302:isolation & purification*; D015398:Signal Transduction
chemical_list: D024682:BRCA2 Protein; C000715593:CBX1 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D056970:Co-Repressor Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C480344:EMSY protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010940:Plant Proteins; D012097:Repressor Proteins; C094763:ZMYND11 protein, human; D000090266:Chromobox Protein Homolog 5