Role of direct interaction in BRCA1 inhibition of estrogen receptor activity.
The BRCA1 gene was previously found to inhibit the transcriptional activity of the estrogen receptor [ER-alpha] in human breast and prostate cancer cell lines. In this study, we found that breast cancer-associated mutations of BRCA1 abolish or reduce its ability to inhibit ER-alpha activity and that domains within the amino- and carboxyl-termini of the BRCA1 protein are required for the inhibition. BRCA1 inhibition of ER-alpha activity was demonstrated under conditions in which a BRCA1 transgene was transiently or stably over-expressed in cell lines with endogenous wild-type BRCA1 and in a breast cancer cell line that lacks endogenous functional BRCA1 (HCC1937). In addition, BRCA1 blocked the expression of two endogenous estrogen-regulated gene products in human breast cancer cells: pS2 and cathepsin D. The BRCA1 protein was found to associate with ER-alpha in vivo and to bind to ER-alpha in vitro, by an estrogen-independent interaction that mapped to the amino-terminal region of BRCA1 (ca. amino acid 1-300) and the conserved carboxyl-terminal activation function [AF-2] domain of ER-alpha. Furthermore, several truncated BRCA1 proteins containing the amino-terminal ER-alpha binding region blocked the ability of the full-length BRCA1 protein to inhibit ER-alpha activity. Our findings suggest that the amino-terminus of BRCA1 interacts with ER-alpha, while the carboxyl-terminus of BRCA1 may function as a transcriptional repression domain. Oncogene (2001) 20, 77 - 87.
Fan
S
S
Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, 270-05 76th Avenue, New Hyde Park, New York, NY 11040, USA.
Ma
Y X
YX
Wang
C
C
Yuan
R Q
RQ
Meng
Q
Q
Wang
J A
JA
Erdos
M
M
Goldberg
I D
ID
Webb
P
P
Kushner
P J
PJ
Pestell
R G
RG
Rosen
E M
EM
D019313:BRCA1 Protein / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D001665:Binding Sites / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002874:Chromosome Mapping; D047628:Estrogen Receptor alpha; D019398:Genes, BRCA1 / Q000235:genetics / Q000502:physiology*; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D019313:BRCA1 Protein; D047628:Estrogen Receptor alpha; D010446:Peptide Fragments; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D005982:Glutathione Transferase