Insulin-like growth factor-I controls BRCA1 gene expression through activation of transcription factor Sp1.
The insulin-like growth factors (IGFs) have a central role in mammary gland growth and differentiation as well as in breast cancer development. The BRCA1 gene encodes a pleiotropic protein that functions as a transcription factor. Germline BRCA1 mutations are associated with inherited predisposition to breast and ovarian cancer and confer a substantially increased risk for developing these neoplasms. Several lines of evidence led us to hypothesize that there is a functional interaction between the BRCA1 and IGF-I systems relevant to breast cancer biology. The present study tested the notion that BRCA1 gene expression is regulated by the IGF-I signaling pathway. Results of Western immunoblotting and RT-PCR analyses show that IGF-I stimulates BRCA1 protein and mRNA levels. Transient transfection experiments using BRCA1 promoter-luciferase reporter constructs reveal that IGF-I enhances BRCA1 promoter activity, suggesting that the effect of IGF-I is mediated at the transcriptional level. In addition, we provide evidence that the Sp1 zinc-finger protein is directly involved in BRCA1 gene transactivation. Combined, our data suggests that, at least part of the biological actions of IGF-I in mammary gland cells may be mediated through BRCA1. Dysregulated BRCA1 expression resulting from aberrant IGF signaling may have important consequences relevant to breast cancer pathogenesis.
Maor
S
S
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel, and Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, USA.
Papa
M Z
MZ
Yarden
R I
RI
Friedman
E
E
Lerenthal
Y
Y
Lee
S W
SW
Mayer
D
D
Werner
H
H
D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D020868:Gene Silencing; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000235:genetics*; D015533:Transcriptional Activation / Q000187:drug effects*
D019313:BRCA1 Protein; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II