Abstract
FOXM1 is frequently overexpressed in cancer, but this has not been studied in a comprehensive manner. We utilized genotype-tissue expression (GTEx) normal and The Cancer Genome Atlas (TCGA) tumor data to define FOXM1 expression, including its isoforms, and to determine the genetic alterations that promote FOXM1 expression in cancer. Additionally, we used human fallopian tube epithelial (FTE) cells to dissect the role of Retinoblastoma (Rb)-E2F and Cyclin E1 in FOXM1 regulation, and a novel human embryonic kidney cell (HEK293T) CRISPR FOXM1 knockout model to define isoform-specific transcriptional programs. FOXM1 expression, at the mRNA and protein level, was significantly elevated in tumors with FOXM1 amplification, p53 inactivation, and Rb-E2F deregulation. FOXM1 expression was remarkably high in testicular germ cell tumors (TGCT), high-grade serous ovarian cancer (HGSC), and basal breast cancer (BBC). FOXM1 expression in cancer was associated with genomic instability, as measured using aneuploidy signatures. FTE models confirmed a role for Rb-E2F signaling in FOXM1 regulation and in particular identified Cyclin E1 as a novel inducer of FOXM1 expression. Among the three FOXM1 isoforms, FOXM1c showed the highest expression in normal and tumor tissues and cancer cell lines. The CRISPR knockout model demonstrated that FOXM1b and FOXM1c are transcriptionally active, while FOXM1a is not. Finally, we were unable to confirm the existence of a FOXM1 auto-regulatory loop. This study provides significant and novel information regarding the frequency, causes, and consequences of elevated FOXM1 expression in human cancer.
Highlights
FOXM1 is a member of the Forkhead box (FOX) transcription factor family, which is unified by a conserved winged helix DNA binding motif [1]
FOXM1 mRNA expression was increased in all The Cancer Genome Atlas (TCGA) cancer types compared to
Based on the interquartile range, the spread of FOXM1 expression varied in some cancer types more than others; e.g., breast cancer (BRCA) has a wide spread while testicular germ cell tumors (TCGT) have a narrow spread (Figure 1A), which could be due to some cancers consisting of more than one clearly defined subtype and having more genetic diversity
Summary
FOXM1 is a member of the Forkhead box (FOX) transcription factor family, which is unified by a conserved winged helix DNA binding motif [1]. FOXM1 plays a key role in proliferation and cell cycle progression through transcriptional activation of a G2/M-specific gene network [2,3,4]. Increased FOXM1 gene expression and its transcriptional signature are detected in many cancer types [5,6,7,8,9]. Pan-cancer analysis identified FOXM1 as the top gene associated with poor prognosis [10]. FOXM1 is a promising therapeutic target for cancer treatment [11,12,13,14,15]. While increased FOXM1 expression is reported in many cancers, we lack an understanding of how FOXM1 copy number, mRNA, and protein expression compare and are associated in pan-cancer
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