title: Genetic determinants of FOXM1 overexpression in epithelial ovarian cancer and functional contribution to cell cycle progression.
abstract: 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.
authors.affiliation: Eppley Institute and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
authors.forename: Carter J
authors.initials: CJ
authors.lastname: Barger
authors.affiliation: Eppley Institute and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
authors.forename: Wa
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Hillman
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
authors.forename: Aimee B
authors.initials: AB
authors.lastname: Stablewski
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Higgins
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada.
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Vanderhyden
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.|Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.|Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
authors.affiliation: Eppley Institute and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Karpf
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D051379:Mice; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000952:Antigens, Polyomavirus Transforming; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: E2F1; FOXM1; Rb; epithelial ovarian cancer; p53