Abstract 1991: FOXM1 expression in epithelial ovarian cancer coincides with gene amplification and functional loss of p53 and Rb and drives G2-M progression and target gene expression

Abstract

Abstract Introduction: According to The Cancer Genome Atlas (TCGA), the FOXM1 transcription factor network is activated in 84% of high-grade serous ovarian cancers (HGS-OC), a common and lethal subtype of epithelial ovarian cancer (EOC). FOXM1 plays a key role in cell cycle progression and genomic stability, and is overexpressed in various malignancies. The goal of this study was to understand the genetic determinants of FOXM1 expression in EOC, and to define its functional role in relevant cell models. Methods: We analyzed FOXM1 gene amplification data in HGS-OC and other cancers using cBioPortal. We determined FOXM1 expression and its relationship to clinico-pathology in a large set of primary EOC tissues. We used primary and immortalized murine (MOSE) and human ovarian surface epithelial (hOSE) cells to determine the contribution of p53, Rb, and E2F1 to FOXM1 expression. We used FOXM1 knockdown and overexpression approaches to dissect its functional contribution to cell cycle progression and target gene activation in OSE and EOC cells. We used human EOC cell lines to assess genetic mechanisms driving the expression of the three known FOXM1 splice variants. Results: The FOXM1 locus was amplified in ∼12% of HGS-OC, greater than any other tumor type examined and suggestive of selective pressure in HGS-OC. FOXM1 mRNA was frequently upregulated in EOC, in association with advanced stage and grade. In MOSE cells, combined knockout of Rb1 and Trp53 synergistically induced Foxm1. In agreement, hOSE cells immortalized with SV40 T antigen (IOSE-SV) showed dramatically higher FOXM1 expression as compared to hOSE immortalized with hTERT. Knockdown experiments revealed that FOXM1 induction in IOSE-SV is partially dependent on E2F1. FOXM1 knockdown in IOSE-SV blocked G2-M transition and downregulated known targets of FOXM1, including CCNB1 and PLK1. Conversely, FOXM1 overexpression in primary hOSE upregulated FOXM1 target genes. FOXM1 expression in EOC cell lines was heterogeneous and the highest expression was observed in cell lines with FOXM1 gene amplification and TP53 and RB1 mutations. The level of expression of FOXM1 splice variants in EOC cell lines was consistently FOXM1c > FOXM1b > FOXM1a, indicating that transcriptionally active isoforms show higher expression. Conclusions: Our data reveal that genetic alterations in TP53 and RB1, along with FOXM1 gene amplification, are critical determinants of FOXM1 expression in EOC. FOXM1 functionally contributes to cell cycle progression in EOC models, likely via the transactivation of gene targets driving G2-M transition. Current studies are dissecting the role of post-translational modifications in FOXM1 activation in EOC, and extending work into relevant human fallopian tube secretory epithelial cell systems. Finally, our findings support the development of FOXM1-targeted therapies for EOC. Citation Format: Carter J. Barger, Wa Zhang, Kunle Odunsi, Adam R. Karpf. FOXM1 expression in epithelial ovarian cancer coincides with gene amplification and functional loss of p53 and Rb and drives G2-M progression and target gene expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1991. doi:10.1158/1538-7445.AM2015-1991