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.
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Authors | Zohar Attias-Geva, Itay Bentov, Dvora Kidron, Keren Amichay, Rive Sarfstein, Ami Fishman, Ilan Bruchim, Haim Werner |
Journal | European journal of cancer (Oxford, England : 1990)
(Eur J Cancer)
Vol. 48
Issue 10
Pg. 1570-80
(Jul 2012)
ISSN: 1879-0852 [Electronic] England |
PMID | 22033326
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011 Elsevier Ltd. All rights reserved. |
Chemical References |
- Biomarkers
- Sp1 Transcription Factor
- TP53 protein, human
- Tumor Suppressor Protein p53
- Receptor, IGF Type 1
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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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