BRCA1 is expressed in uterine serous carcinoma (USC) and controls insulin-like growth factor I receptor (IGF-IR) gene expression in USC cell lines.

Abstract

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.

• Authors: Keren Amichay, Debora Kidron, Zohar Attias-Geva, Hagit Schayek, Rive Sarfstein, Ami Fishman, Haim Werner, Ilan Bruchim
• Journal: International journal of gynecological cancer : official journal of the International Gynecological Cancer Society (Int J Gynecol Cancer) Vol. 22 Issue 5 Pg. 748-54 (Jun 2012) ISSN: 1525-1438 [Electronic] England
• PMID: 22635027 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BRCA1 Protein
• BRCA1 protein, human
• Luciferases
• Receptor, IGF Type 1
• Proto-Oncogene Proteins c-akt

Topics

• BRCA1 Protein (metabolism)
• Blotting, Western
• Carcinoma, Papillary (metabolism, secondary)
• Cell Proliferation
• Cystadenocarcinoma, Serous (metabolism, secondary)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Immunoenzyme Techniques
• Luciferases (metabolism)
• Neoplasm Metastasis
• Phosphorylation
• Prognosis
• Promoter Regions, Genetic (genetics)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor, IGF Type 1 (genetics, metabolism)
• Tumor Cells, Cultured
• Uterine Cervical Neoplasms (metabolism, pathology)