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Cancers 2019, 11(2), 251; https://doi.org/10.3390/cancers11020251

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

1
Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198, USA
2
Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
*
Author to whom correspondence should be addressed.
Received: 24 January 2019 / Revised: 13 February 2019 / Accepted: 18 February 2019 / Published: 21 February 2019
(This article belongs to the Special Issue Fox Proteins and Cancers: Old Proteins with Emerging New Tales)
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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. View Full-Text
Keywords: FOXM1; pan-cancer; gene amplification; genomic instability; Retinoblastoma protein Cyclin E1; fallopian tube epithelial cells; testicular germ cell tumors; high-grade serous ovarian cancer; basal breast cancer FOXM1; pan-cancer; gene amplification; genomic instability; Retinoblastoma protein Cyclin E1; fallopian tube epithelial cells; testicular germ cell tumors; high-grade serous ovarian cancer; basal breast cancer
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Barger, C.J.; Branick, C.; Chee, L.; Karpf, A.R. Pan-Cancer Analyses Reveal Genomic Features of FOXM1 Overexpression in Cancer. Cancers 2019, 11, 251.

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