BRCA1 suppresses insulin-like growth factor-I receptor promoter activity: potential interaction between BRCA1 and Sp1.
The insulin-like growth factor I receptor (IGF-I-R) has an important role in breast cancer etiology. The receptor is overexpressed by most breast cancers, where it functions as a potent antiapoptotic agent. BRCA1 is a tumor suppressor gene that is mutated in a large fraction of familial breast and ovarian cancers. Cotransfection of Saos-2, MCF7, and CHO cells with IGF-I-R promoter constructs driving luciferase reporter genes, and with a BRCA1 expression vector, suppressed promoter activity in a dose-dependent manner. Functional interactions between BRCA1 and Sp1 in the regulation of the IGF-I-R gene were studied in Schneider cells, a Drosophila cell line which lacks endogenous Sp1. In these cells BRCA1 suppressed 45% of the Sp1-induced trans-activation of the IGF-I-R promoter. These results suggest that BRCA1 is capable of suppressing the IGF-I-R promoter in a number of cell lines, thus resulting in low levels of receptor mRNA and protein. Mutant versions of BRCA1 lacking trans-activational activity can potentially derepress the IGF-I-R promoter. Activation of the overexpressed receptor by locally produced or circulating IGFs may be a crucial step in breast and ovarian cancer progression.
Maor
S B
SB
Department of Clinical Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
Abramovitch
S
S
Erdos
M R
MR
Brody
L C
LC
Werner
H
H
D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism*; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D004330:Drosophila / Q000166:cytology; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014162:Transfection
D019313:BRCA1 Protein; D016329:Sp1 Transcription Factor; D017526:Receptor, IGF Type 1