EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer.
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.
Hughes-Davies
Luke
L
Cancer Research UK/Wellcome Trust Institute and Department of Pathology, Tennis Court Road, Cambridge CB2 1QR, United Kingdom. lh205@cus.cam.ac.uk
Huntsman
David
D
Ruas
Margarida
M
Fuks
Francois
F
Bye
Jacqueline
J
Chin
Suet-Feung
SF
Milner
Jonathon
J
Brown
Lindsay A
LA
Hsu
Forrest
F
Gilks
Blake
B
Nielsen
Torsten
T
Schulzer
Michael
M
Chia
Stephen
S
Ragaz
Joseph
J
Cahn
Anthony
A
Linger
Lori
L
Ozdag
Hilal
H
Cattaneo
Elena
E
Jordanova
E S
ES
Schuuring
Edward
E
Yu
David S
DS
Venkitaraman
Ashok
A
Ponder
Bruce
B
Doherty
Aidan
A
Aparicio
Samuel
S
Bentley
David
D
Theillet
Charles
C
Ponting
Chris P
CP
Caldas
Carlos
C
Kouzarides
Tony
T
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
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