The treatment of advanced
prostate cancer (PCa) remains a challenge. Identification of new molecular mechanisms that regulate PCa initiation and progression would provide targets for the development of new
cancer treatments. The Foxm1
transcription factor is highly up-regulated in
tumor cells, inflammatory cells, and cells of tumor microenvironment. However, its functions in different cell populations of PCa lesions are unknown. To determine the role of Foxm1 in
tumor cells during PCa development, we generated two novel transgenic mouse models, one exhibiting Foxm1 gain-of-function and one exhibiting Foxm1 loss-of-function under control of the prostate epithelial-specific
Probasin promoter. In the transgenic
adenocarcinoma mouse prostate (TRAMP) model of PCa that uses SV40
large T antigen to induce PCa, loss of Foxm1 decreased
tumor growth and
metastasis. Decreased prostate
tumorigenesis was associated with a decrease in
tumor cell proliferation and the down-regulation of genes critical for cell proliferation and
tumor metastasis, including Cdc25b,
Cyclin B1, Plk-1, Lox, and
Versican. In addition,
tumor-associated angiogenesis was decreased, coinciding with reduced
Vegf-A expression. The
mRNA and
protein levels of 11β-Hsd2, an
enzyme playing an important role in
tumor cell proliferation, were down-regulated in Foxm1-deficient PCa
tumors in vivo and in Foxm1-depleted TRAMP C2 cells in vitro. Foxm1 bound to, and increased transcriptional activity of, the mouse 11β-Hsd2 promoter through the -892/-879 region, indicating that 11β-Hsd2 was a direct transcriptional target of Foxm1. Without TRAMP, overexpression of Foxm1 either alone or in combination with inhibition of a p19(ARF)
tumor suppressor caused a robust epithelial
hyperplasia, but was insufficient to induce progression from
hyperplasia to PCa. Foxm1 expression in prostate epithelial cells is critical for prostate
carcinogenesis, suggesting that inhibition of Foxm1 is a promising therapeutic approach for
prostate cancer chemotherapy.