Elevated insulin-like growth factor-I receptor (IGF-IR) levels in primary breast tumors associated with BRCA1 mutations.
The insulin-like growth factors (IGFs) play a pivotal role in breast cancer. Inherited predisposition to breast and ovarian cancer is associated with germline BRCA1/BRCA2 mutations. To evaluate the impact of BRCA1 mutations on IGF-IR gene expression, we performed an immunohistochemical analysis of IGF-IR in primary breast tumors from BRCA1 mutation carriers and non-carriers. Results obtained revealed a significant elevation in IGF-IR levels in tumors from BRCA1 mutation carriers compared with non-carriers. To assess the potential inhibitory role of BRCA1 on IGF-IR levels, we infected the BRCA1-deficient HCC1937 cell line with a BRCA1-encoding adenoviral vector. Results of Western blots showed that BRCA1 induced a large reduction in endogenous IGF-IR levels. Furthermore, results of chromatin immunoprecipitation assays indicated that the mechanism of action of BRCA1 involves interaction with Sp1, a potent transactivator of the IGF-IR gene. In conclusion, our data suggests that the IGF-IR gene is a physiologically relevant downstream target for BRCA1 action.
Maor
Sharon
S
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Yosepovich
Ady
A
Papa
Moshe Z
MZ
Yarden
Ronit I
RI
Mayer
Doris
D
Friedman
Eitan
E
Werner
Haim
H
D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D005260:Female; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D019313:BRCA1 Protein; D016329:Sp1 Transcription Factor; D017526:Receptor, IGF Type 1