Genetic determinants of FOXM1 overexpression in epithelial ovarian cancer and functional contribution to cell cycle progression
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Carter J. Barger1, Wa Zhang1, Joanna Hillman2, Aimee B. Stablewski2, Michael J. Higgins2, Barbara C. Vanderhyden3, Kunle Odunsi4,5,6, Adam R. Karpf1
1Eppley Institute and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA
2Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA
3Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada
4Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA
5Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA
6Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA
Adam R. Karpf, e-mail: [email protected]
Keywords: FOXM1, epithelial ovarian cancer, p53, Rb, E2F1
Received: March 17, 2015 Accepted: July 06, 2015 Published: July 16, 2015
The FOXM1 transcription factor network is frequently activated in high-grade serous ovarian cancer (HGSOC), the most common and lethal subtype of epithelial ovarian cancer (EOC). We used primary human EOC tissues, HGSOC cell lines, mouse and human ovarian surface epithelial (OSE) cells, and a murine transgenic ovarian cancer model to investigate genetic determinants of FOXM1 overexpression in EOC, and to begin to define its functional contribution to disease pathology. The Cancer Genome Atlas (TCGA) data indicated that the FOXM1 locus is amplified in ~12% of HGSOC, greater than any other tumor type examined, and that FOXM1 amplification correlates with increased expression and poor survival. In an independent set of primary EOC tissues, FOXM1 expression correlated with advanced stage and grade. Of the three known FOXM1 isoforms, FOXM1c showed highest expression in EOC. In murine OSE cells, combined knockout of Rb1 and Trp53 synergistically induced FOXM1. Consistently, human OSE cells immortalized with SV40 Large T antigen (IOSE-SV) had significantly higher FOXM1 expression than OSE immortalized with hTERT (IOSE-T). FOXM1 was overexpressed in murine ovarian tumors driven by combined Rb1/Trp53 disruption. FOXM1 induction in IOSE-SV cells was partially dependent on E2F1, and FOXM1 expression correlated with E2F1 expression in human EOC tissues. Finally, FOXM1 functionally contributed to cell cycle progression and relevant target gene expression in human OSE and HGSOC cell models. In summary, gene amplification, p53 and Rb disruption, and E2F1 activation drive FOXM1 expression in EOC, and FOXM1 promotes cell cycle progression in EOC cell models.
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