Abstract AP12: FOXM1 INDUCES DNA REPLICATION STRESS AND PROMOTES GENOMIC INSTABILITY DOWNSTREAM OF CYCLIN E1 IN HIGH-GRADE SEROUS OVARIAN CANCER

Abstract

Abstract PURPOSE: Genomic instability (GI) is a hallmark of high-grade serous ovarian cancer (HGSC), and induction of the FOXM1 transcription factor regulatory network is the second most frequent genetic alteration in HGSC. FOXM1 expression is associated with cancer GI, but the mechanistic link is unknown. DNA replication stress (DRS), which involves altered replication fork dynamics, is a key contributor to cancer GI. FOXM1 and cyclin E1 (CCNE1) are both expressed in STIC lesions in the fallopian tube epithelium (FTE), and CCNE1-CDK2 enhances FOXM1 transcriptional activity. Based on these observations, we hypothesized that: 1) FOXM1 is linked to cancer GI through the induction of DRS, and 2) FOXM1 promotes GI downstream of CCNE1, by promoting unscheduled M phase entry in cells that have not completed DNA synthesis. METHODS: We determined associations between FOXM1 and markers of DRS and GI in TCGA HGSC data. We overexpressed FOXM1c and a DNA binding domain mutant (DBD) in immortalized FTE cells and characterized the impact on DRS, DNA replication, and DNA damage. We determined the impact of CCNE1 on FOXM1 expression in immortalized FTE cells. We determined the combined effect of CCNE1 and FOXM1 on GI in FTE cells. RESULTS: FOXM1 was significantly associated with markers of DRS (CHK1-Ser345) and GI (fractional copy number altered genome (CNA)) in TCGA HGSC data. FOXM1 expression, but not its DBD mutant, induced biomarkers of DRS and DNA damage in hTERT/mutant Tp53 immortalized FTE cells. Unexpectedly, FOXM1c increased DNA replication fork rate in FTE cells. Increased fork rate is a novel and recently recognized cause of DRS. CCNE1 expression in FTE cells induced and activated FOXM1, promoting mitotic entry. FOXM1 and CCNE1 co-expression in FTE cells induced an expression signature of GI, and TCGA HGSC tumors with FOXM1 and CCNE1 co-expression showed significantly increased GI. CONCLUSIONS: We demonstrate that FOXM1 induces DRS and DNA damage in FTE cells, providing an explanation for the known link between FOXM1 and GI. Notably, FOXM1 induces a novel form of DRS involving increased replication fork rate. We show that CCNE1 activates FOXM1, which in turn promotes mitotic entry and GI. These data reveal a potentially major form of oncogenic collaboration in HGSC, and has implications for HGSC treatment approaches that promote DRS or inhibit the cellular DRS response. . Citation Format: Carter J Barger, Kajal Biswas, Linda Chee, Ronny Drapkin, Shyam Sharan, Adam R. Karpf. FOXM1 INDUCES DNA REPLICATION STRESS AND PROMOTES GENOMIC INSTABILITY DOWNSTREAM OF CYCLIN E1 IN HIGH-GRADE SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP12.