E2Fs mediate a fundamental cell-cycle deregulation in high-grade serous ovarian carcinomas

• Published in: The Journal of pathology Vol. 217; no. 1; pp. 14 - 20
• Main Authors: De Meyer, T, Bijsmans, ITGW, Van de Vijver, KK, Bekaert, S, Oosting, J, Van Criekinge, W, van Engeland, M, Sieben, NLG
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 2009; Wiley
• Subjects: Biological and medical sciences; Cell Cycle; Cystadenocarcinoma, Serous - genetics; Cystadenocarcinoma, Serous - metabolism; Cystadenocarcinoma, Serous - pathology; Disease Progression; E2F; E2F1 Transcription Factor - genetics; E2F1 Transcription Factor - physiology; Female; Female genital diseases; Gene Expression Profiling - methods; Genes, p53; Gynecology. Andrology. Obstetrics; Humans; Investigative techniques, diagnostic techniques (general aspects); Medical sciences; microarray expression analysis; Mutation; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Oligonucleotide Array Sequence Analysis - methods; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; progression; Reverse Transcriptase Polymerase Chain Reaction - methods; serous borderline tumour; serous ovarian carcinoma; Signal Transduction; TP53; TP53, mutation; Tumors; tumour of low malignant potential; Up-Regulation; Ovary carcinoma; Ovary cancer; Malignancy; mutation; progression; Malignant tumor; Female genital diseases; High grade; Ovarian diseases; Anatomic pathology; TP53 Gene; Transcription factor E2F; Low malignancy; Cell cycle; Serous carcinoma; Genetics; Borderline tumor; Mutation; serous ovarian carcinoma; serous borderline tumour; microarray expression analysis; E2F; tumour of low malignant potential; TP53; Cancer; Tumor suppressor gene; High malignancy
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2452

Several studies described a role for the E2F/Rb pathway in ovarian serous carcinomas (SCAs). Since E2F/Rb pathway deregulation is a general hallmark of human cancer, it remains unclear whether this deregulation is of particular importance in SCAs or whether it reflects a common oncological feature. Here, we have clarified this issue by the examination of microarray expression profiles of SCAs and particularly by the comparison with another, less malignant, ovarian cancer type, serous borderline tumours (SBTs). Results were validated by quantitative RT-PCR, both on the microarray samples and on an independent panel, and TP53 mutation analysis was performed. This integrated analysis revealed a significant increase in the expression of the transcription factors E2F1 and E2F3 in SCAs, when compared to SBTs. This was associated with vast overexpression of E2F target genes in SCAs compared to SBTs. High-grade SCAs in particular exhibited a major deregulated E2F target expression pattern. Generally, overexpression of E2F targets in SCAs appeared to be well structured since those targets considered negative regulators of the cell cycle or promoters of apoptosis were usually not overexpressed in SCAs. Similar to E2F target deregulation, TP53 mutations were identified in SCA3s, to a lesser extent in SCA1s, and not in SBTs. These results suggest that a structured, generally up-regulated E2F transcription factor activity is associated with a global cell-cycle disturbance in high-grade SCAs and exceeds typical E2F/Rb pathway disruption in tumours, at least compared with SBTs. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.