Regulation of Prostate Cancer Progression by the AHR

University Of Wisconsin Madison, Madison WI

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Abstract

DESCRIPTION (provided by applicant): The aryl hydrocarbon receptor (AhR) is a signal transduction protein that binds chlorinated dioxins and other xenobiotics and mediates their effects on gene expression in various organs including the prostate. We have utilized transgenic adenocarcinoma mouse prostate (TRAMP) mice to test the hypothesis that alterations in AhR signaling pathway can affect prostate cancer development. TRAMP mice on a C57BI/6J backgroundi rarely develop macroscopic prostate cancer in our lab (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). These preliminary results demonstrate that the AhR can greatly affect prostate cancer progression, and suggest that Ahr may be involved in prostate tumor suppression. One objective of the proposed research is to elucidate the mechanisms by which AhR regulates prostate tumor progression. The effects of Ahr genotype on microscopic and macroscopic prostate cancer development will be systematically characterized in TRAMP mice at 5-week intervals starting at 5 weeks of age. Large T antigen and AhR levels will be investigated as they relate to prostate pathology. Loss of heterozygosity of the AhR gene will also be analyzed. We will also test the hypothesis that activation of the AhR signaling pathway by a selective AhR: modulator (6-methyl-1, 3,8-trichlorodibenzofuran; 6-MCDF) can inhibit prostate cancer. The proposed studies will help elucidate the biochemical basis for effects of the AhR signaling pathway on prostate cancer, and begin in vivo testing of selective AhR agonists as potential new therapeutics for treating this disease.