BRCA2 cooperates with histone acetyltransferases in androgen receptor-mediated transcription.
Germ-line mutations of the BRCA2 tumor suppressor gene greatly increase the risk of developing breast and ovarian cancers. Here, we show that wild-type BRCA2, but not a tumor-specific truncated mutant BRCA2, synergizes with the nuclear receptor coactivator p160 GRIP1 to enhance transcriptional activation by androgen receptor (AR). BRCA2 not only associates with AR and GRIP1 but also cooperates with both the histone acetyltransferase P/CAF and BRCA1 to enhance AR- and GRIP1-mediated transactivation. As such, BRCA2 can exert its tumor suppressor function, in part, by modulating androgen signaling, which has been shown to be antiproliferative in a subset of breast cancer cells and particularly implicated in male breast tumors.
Shin
Sook
S
Laboratory of Genetics, The Salk Institute for Biological Sciences, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Verma
Inder M
IM
D000123:Acetyltransferases / Q000378:metabolism*; D019313:BRCA1 Protein / Q000378:metabolism; D024682:BRCA2 Protein / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D018567:Breast Neoplasms, Male / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D004260:DNA Repair; D005260:Female; D024522:Genes, BRCA2; D051548:Histone Acetyltransferases; D006801:Humans; D008297:Male; D009154:Mutation; D051958:Nuclear Receptor Coactivator 2; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D017384:Sequence Deletion; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism; D015533:Transcriptional Activation; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D018797:Cell Cycle Proteins; D051548:Histone Acetyltransferases; D051958:Nuclear Receptor Coactivator 2; D011944:Receptors, Androgen; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C498001:NCOA2 protein, human