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

Oncogene volume 33, pages 4424–4432 (2014)Cite this article

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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.

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Acknowledgements

This work was supported by research grants from the National Institutes of Health/National Cancer Institute (P50 CA105009, U01 CA152990, and R21 CA156021), the Ovarian Cancer Research Fund, The Mary Kay Foundation, The Tina Brozman Foundation, The Robert and Debra First Fund, the Gamel Family Fund for Ovarian Cancer, the Marsha Rivkin Foundation Scientific Scholar Award, the AACR- George and Patricia Sehl Fellowship for Cancer Genetics Research, the American Physicians Fellowship for Medicine in Israel—Claire and Emmanuel G. Rosenblatt Foundation Grant, The Israel Science Foundation Legacy Heritage Clinical Research Initiative, The Israel Cancer Research Fund Clinical Research Career Development Award and the Chaim Sheba Medical Center Dr Pinchas Bornstein Talpiot Medical Leadership Program.We thank Drs. John Quackenbush, Massimo Loda, Keith Ligon and Sekhar Duraisamy, Dana-Farber Cancer Institute, for their suggestions and generous assistance with reagents and bioinformatics; Dr Ravid Straussman, the Broad Institute, for his guidance with methylation detection; Dr Sol Efroni and Rotem Ben-Hamo, Bar llan University, Israel, for bioinformatic support; and The Chaim Sheba Tissue Bank.

DISCLAIMER

Some results published here are based upon data generated by The Cancer Genome Atlas Pilot Project (http://cancergenome.nih.gov).

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Author notes

  1. K Levanon and S Sapoznik: These authors contributed equally to this work.

Authors and Affiliations

  1. The Dr Pinchas Borenstein Talpiot Medical Leadership Program 2012, Sheba Cancer Research Center, Chaim Sheba Medical Center, Ramat Gan, Israel

    K Levanon

  2. Department of Medical Oncology, Dana-Farber Cancer Institute,

    K Levanon & R I Drapkin

  3. Dana-Farber Cancer Institute, Boston, MA, USA

    K Levanon & R I Drapkin

  4. Sheba Cancer Research Center; Chaim Sheba Medical Center,

    S Sapoznik, K Bahar-Shany & H Brand

  5. Chaim Sheba Medical Center, Ramat Gan, Israel

    S Sapoznik, K Bahar-Shany & H Brand

  6. Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Israel

    H Brand

  7. Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan, Israel

    R Shapira-Frommer

  8. Department of Gynecologic Oncology, Chaim Sheba Medical Center, Ramat Gan, Israel

    J Korach & A H Ligon

  9. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    M S Hirsch, M H Roh & R I Drapkin

  10. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    A Miron & J F Liu

  11. Harvard Medical School, Boston, MA, USA

    J F Liu, A H Ligon & R I Drapkin

  12. Center of Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA

    N Vena, A H Ligon, S Fotheringham, D Bailey & R J Flavin

  13. Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA

    M J Birrer

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Correspondence to K Levanon.

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Levanon, K., Sapoznik, S., Bahar-Shany, K. et al. FOXO3a loss is a frequent early event in high-grade pelvic serous carcinogenesis. Oncogene 33, 4424–4432 (2014). https://doi.org/10.1038/onc.2013.394

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