The
aryl hydrocarbon receptor (AhR) is a
basic-helix-loop-helix transcription factor that binds halogenated
aromatic hydrocarbons, polycyclic aromatic hydrocarbons, and endogenous compounds. We previously reported that AhR null (Ahr(-/-)) transgenic
adenocarcinoma of the mouse prostate (TRAMP) mice on a C57BL/6J background develop prostate
tumors with much greater frequency than AhR wild-type (Ahr(+/+)) TRAMP mice, suggesting that the AhR has
tumor suppressor properties. Because AhR signaling pathway inactivation increased susceptibility to prostate
tumorigenesis, we tested the hypothesis that a selective AhR modulator (SAhRM),
6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF), can protect against prostate
tumorigenesis. TRAMP mice on the standard C57BL/6JxFVB genetic background were fed 0, 10, or 40mg 6-
MCDF/kg diet beginning at 8 weeks of age.
Tumor incidence, pelvic
lymph node metastasis, and serum
vascular endothelial growth factor (
VEGF) concentrations were determined at 140 days of age. Prostate
tumor incidence and size were not significantly reduced in mice fed 6-MCDF. However, the frequency of pelvic
lymph node metastasis was reduced fivefold in mice fed the 40mg 6-
MCDF/kg diet. Serum
VEGF concentrations were also reduced by 6-MCDF treatment, particularly in mice without prostate
tumors, and 6-MCDF was shown to act directly on cultured prostates to inhibit
VEGF secretion. Together, these results suggest that 6-MCDF inhibits
metastasis, in part, by inhibiting prostatic
VEGF production prior to
tumor formation. This is the first report that 6-MCDF can confer protection against
prostate cancer in vivo.