Genetic determinants of FOXM1 overexpression in epithelial ovarian cancer and functional contribution to cell cycle progression

The FOXM1 transcription factor network is frequently activated in high-grade serous ovarian cancer (HGSOC), the most common and lethal subtype of epithelial ovarian cancer (EOC). We used primary human EOC tissues, HGSOC cell lines, mouse and human ovarian surface epithelial (OSE) cells, and a murine transgenic ovarian cancer model to investigate genetic determinants of FOXM1 overexpression in EOC, and to begin to define its functional contribution to disease pathology. The Cancer Genome Atlas (TCGA) data indicated that the FOXM1 locus is amplified in ~12% of HGSOC, greater than any other tumor type examined, and that FOXM1 amplification correlates with increased expression and poor survival. In an independent set of primary EOC tissues, FOXM1 expression correlated with advanced stage and grade. Of the three known FOXM1 isoforms, FOXM1c showed highest expression in EOC. In murine OSE cells, combined knockout of Rb1 and Trp53 synergistically induced FOXM1. Consistently, human OSE cells immortalized with SV40 Large T antigen (IOSE-SV) had significantly higher FOXM1 expression than OSE immortalized with hTERT (IOSE-T). FOXM1 was overexpressed in murine ovarian tumors driven by combined Rb1/Trp53 disruption. FOXM1 induction in IOSE-SV cells was partially dependent on E2F1, and FOXM1 expression correlated with E2F1 expression in human EOC tissues. Finally, FOXM1 functionally contributed to cell cycle progression and relevant target gene expression in human OSE and HGSOC cell models. In summary, gene amplification, p53 and Rb disruption, and E2F1 activation drive FOXM1 expression in EOC, and FOXM1 promotes cell cycle progression in EOC cell models.

[1]  T. Kalin,et al.  Is there potential to target FOXM1 for ‘undruggable’ lung cancers? , 2015, Expert opinion on therapeutic targets.

[2]  Joshy George,et al.  Whole–genome characterization of chemoresistant ovarian cancer , 2015, Nature.

[3]  Christopher M. DeBoever,et al.  Systematic transcriptome analysis reveals tumor-specific isoforms for ovarian cancer diagnosis and therapy , 2015, Proceedings of the National Academy of Sciences.

[4]  W. Ahrens,et al.  The 12p13.33/RAD52 Locus and Genetic Susceptibility to Squamous Cell Cancers of Upper Aerodigestive Tract , 2015, PloS one.

[5]  W. Chiu,et al.  FOXM1 confers to epithelial-mesenchymal transition, stemness and chemoresistance in epithelial ovarian carcinoma cells , 2014, Oncotarget.

[6]  E. Lam,et al.  Overexpression of Forkhead Box Protein M1 (FOXM1) in Ovarian Cancer Correlates with Poor Patient Survival and Contributes to Paclitaxel Resistance , 2014, PloS one.

[7]  Michael V. Gormally,et al.  Suppression of the FOXM1 transcriptional program via novel small molecule inhibition , 2014, Nature Communications.

[8]  J. Chien,et al.  Targeting of mutant p53-induced FoxM1 with thiostrepton induces cytotoxicity and enhances carboplatin sensitivity in cancer cells , 2014, Oncotarget.

[9]  Yi Wang,et al.  Overexpression of FOXM1 predicts poor prognosis and promotes cancer cell proliferation, migration and invasion in epithelial ovarian cancer , 2014, Journal of Translational Medicine.

[10]  Ting Liu,et al.  FOXM1 Modulates Cisplatin Sensitivity by Regulating EXO1 in Ovarian Cancer , 2014, PloS one.

[11]  B. Vanderhyden,et al.  A New Spontaneously Transformed Syngeneic Model of High-Grade Serous Ovarian Cancer with a Tumor-Initiating Cell Population , 2014, Front. Oncol..

[12]  David D L Bowtell,et al.  Cyclin E1 deregulation occurs early in secretory cell transformation to promote formation of fallopian tube-derived high-grade serous ovarian cancers. , 2014, Cancer research.

[13]  W. Hahn,et al.  Synthetic lethality between CCNE1 amplification and loss of BRCA1 , 2013, Proceedings of the National Academy of Sciences.

[14]  R. Drapkin,et al.  FOXO3a loss is a frequent early event in high-grade pelvic serous carcinogenesis , 2013, Oncogene.

[15]  Chris Sander,et al.  Emerging landscape of oncogenic signatures across human cancers , 2013, Nature Genetics.

[16]  C. Sander,et al.  Evaluating cell lines as tumour models by comparison of genomic profiles , 2013, Nature Communications.

[17]  Chen Huang,et al.  Dysregulated expression of FOXM1 isoforms drives progression of pancreatic cancer. , 2013, Cancer research.

[18]  Benjamin E. Gross,et al.  Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal , 2013, Science Signaling.

[19]  A. Gartel,et al.  FOX(M1) News—It Is Cancer , 2013, Molecular Cancer Therapeutics.

[20]  K. Yao,et al.  FOXM1b, which is present at elevated levels in cancer cells, has a greater transforming potential than FOXM1c , 2013, Front. Oncol..

[21]  B. Vanderhyden,et al.  Technical challenges and limitations of current mouse models of ovarian cancer , 2012, Journal of Ovarian Research.

[22]  X. Chen,et al.  The Forkhead Transcription Factor FOXM1 Controls Cell Cycle-Dependent Gene Expression through an Atypical Chromatin Binding Mechanism , 2012, Molecular and Cellular Biology.

[23]  A. Mencalha,et al.  Forkhead Box M1 (FoxM1) Gene Is a New STAT3 Transcriptional Factor Target and Is Essential for Proliferation, Survival and DNA Repair of K562 Cell Line , 2012, PloS one.

[24]  Kevin W Eliceiri,et al.  NIH Image to ImageJ: 25 years of image analysis , 2012, Nature Methods.

[25]  Benjamin E. Gross,et al.  The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. , 2012, Cancer discovery.

[26]  U. Moll,et al.  Links between mutant p53 and genomic instability , 2012, Journal of cellular biochemistry.

[27]  S. Gygi,et al.  A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. , 2011, Cancer cell.

[28]  Kenneth P. Nephew,et al.  Rethinking ovarian cancer: recommendations for improving outcomes , 2011, Nature Reviews Cancer.

[29]  A. Gartel,et al.  Micelle-Encapsulated Thiostrepton as an Effective Nanomedicine for Inhibiting Tumor Growth and for Suppressing FOXM1 in Human Xenografts , 2011, Molecular Cancer Therapeutics.

[30]  Benjamin J. Raphael,et al.  Integrated Genomic Analyses of Ovarian Carcinoma , 2011, Nature.

[31]  R. Lea,et al.  Integrative genomic profiling reveals conserved genetic mechanisms for tumorigenesis in common entities of non‐Hodgkin's lymphoma , 2011, Genes, Chromosomes and Cancer.

[32]  Lara J. Monteiro,et al.  ATM and p53 Regulate FOXM1 Expression via E2F in Breast Cancer Epirubicin Treatment and Resistance , 2011, Molecular Cancer Therapeutics.

[33]  B. Scheithauer,et al.  Array-Based Comparative Genomic Hybridization Identifies CDK4 and FOXM1 Alterations as Independent Predictors of Survival in Malignant Peripheral Nerve Sheath Tumor , 2011, Clinical Cancer Research.

[34]  K. Odunsi,et al.  Coordinated Cancer Germline Antigen Promoter and Global DNA Hypomethylation in Ovarian Cancer: Association with the BORIS/CTCF Expression Ratio and Advanced Stage , 2011, Clinical Cancer Research.

[35]  Helga Thorvaldsdóttir,et al.  Integrative Genomics Viewer , 2011, Nature Biotechnology.

[36]  M. Teh,et al.  Upregulation of FOXM1 induces genomic instability in human epidermal keratinocytes , 2010, Molecular Cancer.

[37]  B. Vanderhyden,et al.  Conditional Inactivation of Brca1, p53 and Rb in Mouse Ovaries Results in the Development of Leiomyosarcomas , 2009, PloS one.

[38]  A. Barsotti,et al.  Pro-proliferative FoxM1 is a target of p53-mediated repression , 2009, Oncogene.

[39]  A. Gartel,et al.  p53 negatively regulates expression of FoxM1 , 2009, Cell cycle.

[40]  O. Gangisetty,et al.  Distinct Roles for Histone Methyltransferases G9a and GLP in Cancer Germ-Line Antigen Gene Regulation in Human Cancer Cells and Murine Embryonic Stem Cells , 2009, Molecular Cancer Research.

[41]  Robert C. Bast,et al.  The biology of ovarian cancer: new opportunities for translation , 2009, Nature Reviews Cancer.

[42]  I. Shih,et al.  Analysis of DNA copy number alterations in ovarian serous tumors identifies new molecular genetic changes in low-grade and high-grade carcinomas. , 2009, Cancer research.

[43]  E. Lam,et al.  Gefitinib (Iressa) represses FOXM1 expression via FOXO3a in breast cancer , 2009, Molecular Cancer Therapeutics.

[44]  L. Xia,et al.  Transcriptional up‐regulation of FoxM1 in response to hypoxia is mediated by HIF‐1 , 2009, Journal of cellular biochemistry.

[45]  Mark J. Murphy,et al.  C‐Myc and its target FoxM1 are critical downstream effectors of constitutive androstane receptor (CAR) mediated direct liver hyperplasia , 2008, Hepatology.

[46]  Hao Li,et al.  Plk1-dependent phosphorylation of FoxM1 regulates a transcriptional programme required for mitotic progression , 2008, Nature Cell Biology.

[47]  A. Tyner,et al.  FoxM1 Regulates Transcription of JNK1 to Promote the G1/S Transition and Tumor Cell Invasiveness* , 2008, Journal of Biological Chemistry.

[48]  K. Yao,et al.  Over‐expression of FOXM1 transcription factor is associated with cervical cancer progression and pathogenesis , 2008, The Journal of pathology.

[49]  A. Tyner,et al.  Anaphase-Promoting Complex/Cyclosome-Cdh1-Mediated Proteolysis of the Forkhead Box M1 Transcription Factor Is Critical for Regulated Entry into S Phase , 2008, Molecular and Cellular Biology.

[50]  E. Lander,et al.  Assessing the significance of chromosomal aberrations in cancer: Methodology and application to glioma , 2007, Proceedings of the National Academy of Sciences.

[51]  E. Lam,et al.  The emerging roles of forkhead box (Fox) proteins in cancer , 2007, Nature Reviews Cancer.

[52]  I. Jacobs,et al.  Human ovarian surface epithelial cells immortalized with hTERT maintain functional pRb and p53 expression , 2007, Cell proliferation.

[53]  Zhiwei Wang,et al.  Down-regulation of Forkhead Box M1 transcription factor leads to the inhibition of invasion and angiogenesis of pancreatic cancer cells. , 2007, Cancer research.

[54]  A. Gartel,et al.  Identification of a chemical inhibitor of the oncogenic transcription factor forkhead box M1. , 2006, Cancer research.

[55]  Z. Szallasi,et al.  A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers , 2006, Nature Genetics.

[56]  Vladimir Petrovic,et al.  Forkhead Box M1 Regulates the Transcriptional Network of Genes Essential for Mitotic Progression and Genes Encoding the SCF (Skp2-Cks1) Ubiquitin Ligase , 2005, Molecular and Cellular Biology.

[57]  M. Follettie,et al.  Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe. , 2005, Cancer research.

[58]  A. Cheung,et al.  Raf/MEK/MAPK signaling stimulates the nuclear translocation and transactivating activity of FOXM1c , 2005, Journal of Cell Science.

[59]  Hans Clevers,et al.  FoxM1 is required for execution of the mitotic programme and chromosome stability , 2005, Nature Cell Biology.

[60]  A. Flesken-Nikitin,et al.  Induction of carcinogenesis by concurrent inactivation of p53 and Rb1 in the mouse ovarian surface epithelium. , 2003, Cancer research.

[61]  M. Teh,et al.  FOXM1 is a downstream target of Gli1 in basal cell carcinomas. , 2002, Cancer research.

[62]  Chong Sze Tong,et al.  Over‐expression of FoxM1 stimulates cyclin B1 expression , 2001, FEBS letters.

[63]  J. Harbour,et al.  The Rb/E2F pathway: expanding roles and emerging paradigms. , 2000, Genes & development.

[64]  H. Clevers,et al.  The winged-helix transcription factor Trident is expressed in actively dividing lymphocytes. , 1997, Immunobiology.

[65]  H. Clevers,et al.  The winged-helix transcription factor Trident is expressed in cycling cells. , 1997, Nucleic acids research.

[66]  K. Odunsi,et al.  DNA methylation-dependent regulation of BORIS/CTCFL expression in ovarian cancer. , 2007, Cancer immunity.

[67]  M. McKay,et al.  Cancer of the ovary. , 1994, The New England journal of medicine.