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

• Published in: European journal of cancer (1990) 2012-07, Vol.48 (10), p.1570-1580
• Main Authors: Attias-Geva, Zohar, Bentov, Itay, Kidron, Dvora, Amichay, Keren, Sarfstein, Rive, Fishman, Ami, Bruchim, Ilan, Werner, Haim
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Biological and medical sciences; biomarkers; Biomarkers - metabolism; Carcinoma; Cystadenocarcinoma, Serous - metabolism; DNA Mutational Analysis; Endometrial cancer; Endometrium; Female; Gene expression; Gene Expression Regulation, Neoplastic; Hematology, Oncology and Palliative Medicine; Humans; IGF-I receptor; Immunohistochemistry - methods; Insulin-like growth factor I; Insulin-like growth factor I receptors; Insulin-like growth factor-I (IGF-I); Insulin-like growth factors; Medical sciences; Metastases; Middle Aged; Models, Biological; Mutation; p53; p53 protein; Pharmacology. Drug treatments; Promoters; Receptor, IGF Type 1 - biosynthesis; Retrospective Studies; Signal Transduction; Sp1 protein; Sp1 Transcription Factor - chemistry; Transcription regulation; Transcriptional Activation; Translation; Tumor Suppressor Protein p53 - metabolism; Tumors; Uterine Neoplasms - metabolism; Uterus; Zinc finger proteins; Zinc Fingers
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2011.09.014

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.