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

Abstract

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/BHTtreated 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 À2566/ À2580 bp region of human Cox-2 promoter.

Identification of an intermediate signature that marks the initial phases of the colorectal adenoma-carcinoma transition

“…Analogously, our results also show that the expression level of FOXM1 is increased both in CRC and CRA compared to NOR. The FOXM1 overexpression is essential for the development of various cancers (38,39) ranging from pancreatic (40), breast (41), non-small cell lung cancer (42) and basal cell carcinoma (43), to colorectal cancer (44). FOXM1 was found to be more intensively expressed in CRA than in CRC (P<0.05).…”

Attenuation of Forkhead signaling by the retinal determination factor DACH1

“…FOX protein function can either promote or inhibit tumorigenesis, and deregulation of FOX protein function in human tumorigenesis may occur by alteration in upstream regulators or genetic events such as mutations of the DBD, or translocations, which often disrupt the DBD (16). FOXM1 is overexpressed in human tumors (13,(17)(18)(19)(20)(21)(22) and promotes tumor growth (18,23,24). Inhibition of FOXM1 expression reduces growth of murine tumors in response to carcinogens, and diminishes DNA replication and mitosis of tumor cells (12,13,17,18).…”

Foxm1 Expression in Prostate Epithelial Cells Is Essential for Prostate Carcinogenesis

“…Our previous studies demonstrated that aberrant overexpression of Foxm1 in all cell types using ubiquitous Rosa26 promoter accelerated prostate carcinogenesis in TRAMP and LADY transgenic mice (31). Prostate cancer lesions contain a heterogeneous population of cells, which includes epithelial, inflammatory (macrophages, granulocytes), and stromal cells, all of each up-regulate Foxm1 expression during cancer formation (51).…”