BRCA1 is expressed in uterine serous carcinoma (USC) and controls insulin-like growth factor I receptor (IGF-IR) gene expression in USC cell lines.
OBJECTIVE
The insulin-like growth factor I receptor (IGF-IR) and BRCA1 affect cell growth and apoptosis. Little information is available about BRCA1 activity on the IGF signaling pathway. This study evaluated the effect of BRCA1 on IGF-IR expression.


METHODS
BRCA1 and IGF-IR immunohistochemistry on archival tissues (35 uterine serous carcinomas [USCs] and 17 metastases) were performed. USPC1 and USPC2 cell lines were transiently cotransfected with an IGF-IR promoter construct driving a luciferase reporter gene and a BRCA1 expression plasmid. Endogenous IGF-IR levels were evaluated by Western immunoblotting.


RESULTS
We found high BRCA1 and IGF-IR protein expression in primary and metastatic USC tumors. All samples were immunostained for BRCA1-71% strongly stained; and 33/35 (94%) were stained positive for IGF-IR-2 (6%) strongly stained. No difference in BRCA1 and IGF-IR staining intensity was noted between BRCA1/2 mutation carriers and noncarriers. Metastatic tumors stained more intensely for BRCA1 than did the primary tumor site (P = 0.041) and with borderline significance for IGF-IR (P = 0.069). BRCA1 and IGF-IR staining did not correlate to survival. BRCA1 expression led to 35% and 54% reduction in IGF-IR promoter activity in the USPC1 and USCP2 cell lines, respectively. Western immunoblotting showed a decline in phosphorylated IGF-IR and phosphorylated AKT in both transiently and stably transfected cells.


CONCLUSIONS
BRCA1 and IGF-IR are highly expressed in USC tumors. BRCA1 suppresses IGF-IR gene expression and activity. These findings suggest a possible biological link between the BRCA1 and the IGF-I signaling pathways in USC. The clinical implications of this association need to be explored.
Gynecologic Oncology Unit, Meir Medical Center, Kfar Saba, Israel.
Keren
K
Amichay
Debora
D
Kidron
Zohar
Z
Attias-Geva
Hagit
H
Schayek
Rive
R
Sarfstein
Ami
A
Fishman
Haim
H
Werner
Ilan
I
Bruchim
D019313:BRCA1 Protein / Q000378:metabolism*; D015153:Blotting, Western; D002291:Carcinoma, Papillary / Q000378:metabolism* / Q000556:secondary; D049109:Cell Proliferation; D018284:Cystadenocarcinoma, Serous / Q000378:metabolism* / Q000556:secondary; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D008156:Luciferases; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt