Pan-Cancer Analyses Reveal Genomic Features of FOXM1 Overexpression in Cancer

Cancers
Carter J BargerAdam R Karpf

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 n...Continue Reading

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Citations

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Datasets Mentioned

BETA
ENST00000342628.6
ENST00000359843.7

Methods Mentioned

BETA
genetic modifications
RNA-seq
PCR
protein assay
electrophoresis
transfection
fluorescence-activated cell sorting
genotyping
transfections

Software Mentioned

BLAST
UCSC TOIL
Primer
Ensembl
TopHat
Trim Galore
Graphpad Prism
Venn Diagrams
QuikChange Primer Design
GraphPad

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