The aryl hydrocarbon receptor (AhR) is a transcription factor that binds chlorinated dioxins, other xenobiotics, and various endogenous chemicals and mediates their effects on gene expression in most organs, including prostate. We have discovered that the AhR signaling pathway can greatly affect the incidence of overt prostate cancer. Transgenic adenocarcinoma mouse prostate (TRAMP) mice on a C57BL/6J background rarely develop macroscopic prostate cancer (1 of 27 mice), but their heterozygous (Ahr +/-) and homozygous (Ahr -/-) AhR mutant TRAMP siblings rapidly develop large tumors (27 of 65 and 10 of 15 mice, respectively). Yet no tumors occur in Ahr +/- or Ahr -/- mice in the absence of the TRAMP transgene. These preliminary results demonstrate that the AhR can greatly affect the progression phase of prostate cancer, and suggest that Ahr may be a tumor suppressor gene. One objective of the proposed research is to elucidate mechanisms by which AhR regulates prostate tumor progression. Effects of Ahr genotype on microscopic and macroscopic prostate cancer development in TRAMP mice will be systematically determined. Hypotheses about the mechanisms responsible for these differences in tumor incidence will be tested by sequentially determining large T antigen, AhR, and androgen receptor expression in Ahr +/+, Ahr +/-, and Ahr -/- TRAMP mice. Loss of heterozygosity analysis on the AhR gene and measurements of androgen receptor gene allele number may also be conducted. The primary mechanistic objective is to test the hypothesis that Ahr genotype, controls prostate tumor progression by controlling neuroendocrine differentiation of prostatic cells. This hypothesis is based on preliminary results from gene expression analysis and immunohistochemical localization studies that neuroendocrine differentiation occurs before poorly differentiated nodules vascularize and therefore may be the key Ahr-regulated event that determines whether poorly differentiated lesions will vascularize and subsequently develop into large tumors. The final objective is to test the hypothesis that selective AhR modulators (SAhRMs) - 6-methyl- 1,3,8-trichlorodibenzofuran (6-MCDF) and indole- 3-carbinol - can inhibit or prevent prostate cancer. These experiments will use Ahr +/+TRAMP mice on the standard C57BL/6 x FVB background. Both SAhRMs inhibit prostate cancer cell proliferation in vitro. The proposed studies will elucidate the biochemical basis for effects of the AhR signaling pathway on prostate cancer and begin the in vivo testing of SAhRMs as a possible new therapeutic strategy for treating this disease. The potential impact on human health is that studies on this newly discovered prostate AhR regulatory mechanism in mice may shed light on AhR-related mechanisms capable of controlling prostate tumor progression (which determines whether men with prostate cancer live with or die from this disease) in humans ? ?
