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p53 Regulates insulin-like growth factor-I receptor gene expression in uterine serous carcinoma and predicts responsiveness to an insulin-like growth factor-I receptor-directed targeted therapy.

Abstract
The role of the insulin-like growth factors (IGF) in endometrial cancer has been well established. The IGF-I receptor (IGF-IR), which mediates the biological actions of IGF-I, is usually overexpressed in endometrial tumours. Uterine serous carcinoma (USC) constitutes a defined histological category among endometrial cancers. Mutation of the p53 gene appears early in the course of the disease and is considered a key event in the initiation of USC. The aim of the present study was to evaluate the potential interactions between p53 and the IGF-IR in USC. In addition, we investigated the role of p53 as a biomarker in IGF-IR targeted therapies. Immunohistochemical analysis in a collection of 35 USC specimens revealed that IGF-IR is highly expressed in primary and metastatic USC. Likewise, p53 was expressed in 85.7% of primary tumours and 100% of metastases. A significant negative correlation between p53 expression and survival was noticed. In addition, using USC-derived cell lines we provide evidence that p53 regulates IGF-IR gene expression via a mechanism that involves repression of the IGF-IR promoter. We show that the mechanism of action of p53 involves interaction with zinc finger protein Sp1, a potent transactivator of the IGF-IR gene. Finally, we demonstrate that USC tumours overexpressing p53 are more likely to benefit from anti-IGF-IR therapies. In summary, we provide evidence that p53 regulates IGF-IR gene expression in USC cells via a mechanism that involves repression of the IGF-IR promoter. The interplay between the p53 and IGF-I signalling pathways is of major basic and translational relevance.
AuthorsZohar Attias-Geva, Itay Bentov, Dvora Kidron, Keren Amichay, Rive Sarfstein, Ami Fishman, Ilan Bruchim, Haim Werner
JournalEuropean journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 48 Issue 10 Pg. 1570-80 (Jul 2012) ISSN: 1879-0852 [Electronic] England
PMID22033326 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 Elsevier Ltd. All rights reserved.
Chemical References
  • Biomarkers
  • Sp1 Transcription Factor
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Receptor, IGF Type 1
Topics
  • Aged
  • Aged, 80 and over
  • Biomarkers (metabolism)
  • Cystadenocarcinoma, Serous (metabolism)
  • DNA Mutational Analysis
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunohistochemistry (methods)
  • Middle Aged
  • Models, Biological
  • Receptor, IGF Type 1 (biosynthesis)
  • Retrospective Studies
  • Signal Transduction
  • Sp1 Transcription Factor (chemistry)
  • Transcriptional Activation
  • Tumor Suppressor Protein p53 (metabolism)
  • Uterine Neoplasms (metabolism)
  • Zinc Fingers

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