The proliferation-specific Forkhead Box M1 (FoxM1 or FoxM1b)
transcription factor is overexpressed in a number of aggressive human
carcinomas. Mouse hepatocytes deficient in FoxM1 fail to proliferate and are highly resistant to developing
carcinogen-induced liver
tumors. We previously developed a transgenic (TG) mouse line in which the ubiquitous Rosa26 promoter was used to drive expression of the human FoxM1b
cDNA transgene in all mouse cell types. To investigate the role of FoxM1b in
prostate cancer progression, we bred Rosa26-FoxM1b mice with both TRAMP and LADY TG mouse models of
prostate cancer. We show that increased expression of FoxM1b accelerated development, proliferation, and growth of prostatic
tumors in both TRAMP and LADY double TG mice. Furthermore, development of prostate
carcinomas in TRAMP/Rosa26-FoxM1b double TG mice required high levels of
FoxM1 protein to overcome sustained expression of the alternative reading frame
tumor suppressor, a potent inhibitor of FoxM1 transcriptional activity. Depletion of FoxM1 levels in
prostate cancer cell lines PC-3, LNCaP, or DU-145 by
small interfering RNA transfection caused significant reduction in proliferation and anchorage-independent growth on soft
agar. This phenotype was associated with increased nuclear levels of the
cyclin-dependent kinase inhibitor
protein p27(Kip1) and diminished expression of S-phase promoting
cyclin A2 and M-phase promoting
cyclin B1 proteins. Finally, we show that elevated levels of
FoxM1 protein correlate with high proliferation rates in human prostate
adenocarcinomas. Our results suggest that the FoxM1
transcription factor regulates development and proliferation of prostate
tumors, and that FoxM1 is a novel target for
prostate cancer treatment.