FOXO3a loss is a frequent early event in high-grade pelvic serous carcinogenesis.

Abstract

Serous ovarian carcinoma is the most lethal gynecological malignancy in Western countries. The molecular events that underlie the development of the disease have been elusive for many years. The recent identification of the fallopian tube secretory epithelial cells (FTSECs) as the cell-of-origin for most cases of this disease has led to studies aimed at elucidating new candidate therapeutic pathways through profiling of normal FTSECs and serous carcinomas. Here we describe the results of transcriptional profiles that identify the loss of the tumor suppressive transcription factor FOXO3a in a vast majority of high-grade serous ovarian carcinomas. We show that FOXO3a loss is a hallmark of the earliest stages of serous carcinogenesis and occurs both at the DNA, RNA and protein levels. We describe several mechanisms responsible for FOXO3a inactivity, including chromosomal deletion (chromosome 6q21), upregulation of miRNA-182 and destabilization by activated PI3K and MEK. The identification of pathways involved in the pathogenesis of ovarian cancer can advance the management of this disease from being dependant on surgery and cytotoxic chemotherapy alone to the era of targeted therapy. Our data strongly suggest FOXO3a as a possible target for clinical intervention.

• Authors: K Levanon, S Sapoznik, K Bahar-Shany, H Brand, R Shapira-Frommer, J Korach, M S Hirsch, M H Roh, A Miron, J F Liu, N Vena, A H Ligon, S Fotheringham, D Bailey, R J Flavin, M J Birrer, R I Drapkin
• Journal: Oncogene (Oncogene) Vol. 33 Issue 35 Pg. 4424-32 (Aug 28 2014) ISSN: 1476-5594 [Electronic] England
• PMID: 24077281 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• FOXO3 protein, human
• Forkhead Box Protein O3
• Forkhead Transcription Factors
• MicroRNAs
• Mirn182 microRNA, human

Topics

• Cell Line, Tumor
• Chromosome Deletion
• Chromosomes, Human, Pair 6
• Cystadenocarcinoma, Serous (metabolism, pathology)
• Fallopian Tubes (metabolism, pathology)
• Female
• Forkhead Box Protein O3
• Forkhead Transcription Factors (genetics, metabolism)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• MAP Kinase Signaling System
• MicroRNAs (genetics)
• Ovarian Neoplasms (metabolism, pathology)