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.

Functional characterization of a panel of high-grade serous ovarian cancer cell lines as representative experimental models of the disease

“…A subsequent study [6] compared 47 cell line molecular profiles to the TCGA data and suggested that the most highly cited cell lines in research papers investigating HGSOC are not the cell lines most likely to actually represent HGSOC. Specifically, out of 47 cell lines used in the analysis, the two most highly cited - SKOV3 and A2780 - had some of the lowest suitability scores for HGSOC and were therefore ranked as “unlikely high grade serous.” A number of the cell lines listed as “likely high-grade serous” in this study have had this status confirmed in other studies using a variety of metrics [5, 7, 9]. Angleiso et al reported a set of molecular features and biomarkers in a panel of ovarian cancer cells establishing their histotype [5].…”

PRAME expression and promoter hypomethylation in epithelial ovarian cancer

“…CNA are the predominant molecular alteration in HGSC and are associated with altered gene expression [4, 38, 39]. The chromosomal location of PRAME is 22q11.22.…”

Mechanisms and Targets Involved in Dissemination of Ovarian Cancer

“…RAB25, a small GTPase, is amplified and upregulated in many ovarian carcinomas and regulates motility, aggressiveness, apoptosis and autophagy (147). Expression of forkhead box M1 (FOXM1), a transcription factor, correlates with poor prognosis as assessed by immunohistochemistry in 158 patients with ovarian carcinoma (148). FOXM1 induces ovarian cancer cell proliferation and migration of HO-8910 ovarian cancer cells, as well as expression of MMP2, MMP9 and VEGFA (148).…”