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

Keren Amichay, Debora Kidron, Zohar Attias-Geva, Hagit Schayek, Rive Sarfstein, Ami Fishman, Haim Werner, Ilan Bruchim

Research output: Contribution to journalArticlepeer-review

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 BRCA1V71% strongly stained; and 33/35 (94%) were stained positive for IGF-IRV2 (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.

Original languageEnglish
Pages (from-to)748-754
Number of pages7
JournalInternational Journal of Gynecological Cancer
Volume22
Issue number5
DOIs
StatePublished - Jun 2012

Keywords

  • BRCA1
  • IGF-I receptor
  • Insulin-like growth factor I (IGF-I)
  • Uterine serous carcinoma

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