Tumor suppressor BRCA1 is expressed in prostate cancer and controls insulin-like growth factor I receptor (IGF-IR) gene transcription in an androgen receptor-dependent manner.
OBJECTIVE
The insulin-like growth factor (IGF) system plays an important role in prostate cancer. The BRCA1 gene encodes a transcription factor with tumor suppressor activity. The involvement of BRCA1 in prostate cancer, however, has not yet been elucidated. The purpose of the present study was to examine the functional correlations between BRCA1 and the IGF system in prostate cancer.


METHODS
An immunohistochemical analysis of BRCA1 was done on tissue microarrays comprising 203 primary prostate cancer specimens. In addition, BRCA1 levels were measured in prostate cancer xenografts and in cell lines representing early stages (P69 cells) and advanced stages (M12 cells) of the disease. The ability of BRCA1 to regulate IGF-I receptor (IGF-IR) expression was studied by coexpression experiments using a BRCA1 expression vector along with an IGF-IR promoter-luciferase reporter.


RESULTS
We found significantly elevated BRCA1 levels in prostate cancer in comparison with histologically normal prostate tissue (P<0.001). In addition, an inverse correlation between BRCA1 and IGF-IR levels was observed in the androgen receptor (AR)-negative prostate cancer-derived P69 and M12 cell lines. Coexpression experiments in M12 cells revealed that BRCA1 was able to suppress IGF-IR promoter activity and endogenous IGF-IR levels. On the other hand, BRCA1 enhanced IGF-IR levels in LNCaP C4-2 cells expressing an endogenous AR.


CONCLUSIONS
We provide evidence that BRCA1 differentially regulates IGF-IR expression in AR-positive and AR-negative prostate cancer cells. The mechanism of action of BRCA1 involves modulation of IGF-IR gene transcription. In addition, immunohistochemical data are consistent with a potential survival role of BRCA1 in prostate cancer.
Schayek
Hagit
H
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Haugk
Kathy
K
Sun
Shihua
S
True
Lawrence D
LD
Plymate
Stephen R
SR
Werner
Haim
H
D000368:Aged; D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
C410798:AR protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D011944:Receptors, Androgen; D017526:Receptor, IGF Type 1