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.
Highlights
70% of epithelial ovarian cancer (EOC) cases are diagnosed at advanced stage; long-term survival for these patients is poor and has not improved significantly in the past three decades [1, 2]
This finding suggests that additional genes located at the amplified region of 12p13.33 may contribute to overall survival (OS) in high-grade serous ovarian cancer (HGSOC), and/or that FOXM1 protein or activation levels may be more relevant than mRNA levels for impacting OS
We investigated the potential role of p53 and Rb in FOXM1 regulation in human ovarian surface epithelial (OSE) cells by measuring FOXM1 expression in hOSE cells immortalized www.impactjournals.com/oncotarget with either SV40 Large T antigen (IOSE-SV), which leads to potent inactivation of p53 and Rb, or hTERT (IOSE-T), which leaves both proteins intact [43]
Summary
70% of EOC cases are diagnosed at advanced stage; long-term survival for these patients is poor and has not improved significantly in the past three decades [1, 2]. While the majority EOC patients are initially responsive to chemotherapy, most patients relapse and current second line therapies are not curative. Increased knowledge of the pathological and genetic underpinnings of EOC and HGSOC, its most common and lethal subtype, are likely to lead to advances in diagnosis and treatment [3]. TCGA recently reported mRNA and miRNA expression, DNA copy number alterations (CNA), DNA promoter methylation, and mutational data for HGSOC, which led to classification into sub-groups based on these molecular criteria [4]. CNA is prominent in HGSOC, and occurs at a higher frequency than in any other TCGA-profiled tumor www.impactjournals.com/oncotarget type [4,5,6]. FOXM1 pathway activation is a highly frequent alteration in HGSOC, second only to TP53 mutation [4]
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