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BRCA1 is Expressed in Uterine Serous Carcinoma (USC) and Controls Insulin-Like Growth Factor I Receptor (IGF-IR) Gene Expression in USC Cell Lines
  1. Keren Amichay, MD*,
  2. Debora Kidron, MD,
  3. Zohar Attias-Geva, PhD,
  4. Hagit Schayek, PhD,
  5. Rive Sarfstein, PhD,
  6. Ami Fishman, MD*,
  7. Haim Werner, PhD and
  8. Ilan Bruchim, MD*
  1. *Gynecologic Oncology Unit,
  2. Department of Pathology, Meir Medical Center, Kfar Saba; and
  3. Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
  1. Address correspondence and reprint requests to Ilan Bruchim, MD, Division of Gynecologic Oncology, Meir Medical Center, Tschernichovsky 59, Kfar Saba, Israel 44281. E-mail: ilan.bruchim@gmail.com.

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.

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

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Footnotes

  • This work received support from the Israel Cancer Research Fund (ICRF, Montreal, Canada).

  • The authors declare that there are no conflicts of interest.

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