Transgenic expression of the forkhead box M1 transcription factor induces formation of lung tumors

Oncogene. 2008 Jul 10;27(30):4137-49. doi: 10.1038/onc.2008.60. Epub 2008 Mar 17.


The forkhead box m1 (Foxm1 or Foxm1b) protein (previously called HFH-11B, Trident, Win or MPP2) is abundantly expressed in human non-small cell lung cancers where it transcriptionally induces expression of genes essential for proliferation of tumor cells. In this study, we used Rosa26-Foxm1 transgenic mice, in which the Rosa26 promoter drives ubiquitous expression of Foxm1 transgene, to identify new signaling pathways regulated by Foxm1. Lung tumors were induced in Rosa26-Foxm1 mice using the 3-methylcholanthrene (MCA)/butylated hydroxytoluene (BHT) lung tumor initiation/promotion protocol. Tumors from MCA/BHT-treated Rosa26-Foxm1 mice displayed a significant increase in the number, size and DNA replication compared to wild-type mice. Elevated tumor formation in Rosa26-Foxm1 transgenic lungs was associated with persistent pulmonary inflammation, macrophage infiltration and increased expression of cyclooxygenase-2 (Cox-2), Cdc25C phosphatase, cyclin E2, chemokine ligands CXCL5, CXCL1 and CCL3, cathepsins and matrix metalloprotease-12. Cell culture experiments with A549 human lung adenocarcinoma cells demonstrated that depletion of Foxm1 by either short interfering RNA transfection or treatment with Foxm1-inhibiting ARF 26-44 peptide significantly reduced Cox-2 expression. In co-transfection experiments, Foxm1 protein-induced Cox-2 promoter activity and directly bound to the -2566/-2580 bp region of human Cox-2 promoter.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / chemically induced
  • Adenoma / genetics*
  • Adenoma / pathology
  • Animals
  • Butylated Hydroxytoluene
  • Cyclooxygenase 2 / genetics
  • DNA Replication / drug effects
  • DNA Replication / genetics
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genetic Predisposition to Disease
  • Humans
  • Lung Neoplasms / chemically induced
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Methylcholanthrene
  • Mice
  • Mice, Transgenic
  • Oligonucleotide Array Sequence Analysis
  • Promoter Regions, Genetic
  • Transfection
  • Tumor Burden
  • Tumor Cells, Cultured


  • Forkhead Box Protein M1
  • Forkhead Transcription Factors
  • Foxm1 protein, mouse
  • Butylated Hydroxytoluene
  • Methylcholanthrene
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2