Graduation Date

Summer 8-17-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Adam R. Karpf, Ph.D.

Abstract

High-grade serous ovarian cancer (HGSC) is the most common and deadly subtype of epithelial ovarian cancer. Understanding the molecular basis of HGSC will improve diagnosis and treatment approaches. The Cancer Genome Atlas (TCGA) discovered that Forkhead Box M1 (FOXM1) transcription factor activation is the second most frequent molecular alteration in HGSC (84% of cases), second only to mutations of TP53 (100%). We subsequently defined several genetic mechanisms that underlie increased FOXM1 expression in HGSC, including genomic amplifications and RB-E2F deregulation, and showed that FOXM1 promotes cell cycle progression in cell models relevant to HGSC.

TCGA analyses revealed that genomic instability, consisting of frequent copy number alterations, as key defining molecular features of HGSC and basal breast, more than any other TCGA cancer type. DNA replication stress results from uncoupling of the replicative helicase and polymerase and is a key mechanism of genomic instability. FOXM1 expression is linked to genomic instability but the underlying mechanism is unclear; induction of DNA replication stress could explain this association. In this context, we revealed novel functions of FOXM1 using fallopian tube epithelial (FTE) cells, an HGSC precursor cell model. We showed that FOXM1 increased DNA fork rate, origin firing, and DNA damage. Furthermore, Cyclin E1 cooperated with FOXM1 to increase its transcriptional activity, which promoted cell cycle progression and genomic instability. In agreement, TCGA HGSC tumors with both FOXM1 and CCNE1 copy number gain show increased FOXM1 and CCNE1 expression and genomic instability.

FOXM1 shares a bidirectional promoter with RHNO1 but this genetic interaction has never been studied in any context. Knowledge of this interaction is important for understanding the molecular mechanism of HGSC. We investigated FOXM1 and RHNO1 expression using large-scale genomic datasets from normal and pan-cancer tissues and validated these findings with HGSC cell lines and tissues. FOXM1 and RHNO1 showed a highly significant correlation in all comparisons suggesting a potential for cooperativity. Importantly, we showed that FOXM1 and RHNO1 cooperate to promote cell survival and chemoresistance in HGSC cells. Collectively, these studies support in vivo studies focusing on the cooperativity of FOXM1 and RHNO1 bidirectional gene partners, to further understand their contribution to HGSC development and progression.

Available for download on Saturday, June 13, 2020

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