Continuous AhR Activity Accelerates Prostate Cancer Progression in African-American Men

Recent studies demonstrate that for men with clinically localized, non-metastatic high-risk prostate cancer PCa receiving long-term androgen deprivation therapy ADT and dose-escalated radiotherapy RT, a pre-RT PSA value greater than 0.5ngml after ADT predicts for decreased time to distant metastases. African-American AA men were significantly associated with failure to achieve a pre-RT PSA value less than 0.5 ngml. These elevated PSA levels are a direct result of sustained androgen receptor signaling despite ADT. AA men would benefit greatly from more potent anti-androgenic therapies in combination with radiation. Several independent studies have shown that the aryl hydrocarbon receptor AhR can regulate androgen receptor signaling. AhR has been widely studied for mediating the carcinogenic responses to environmental toxins and its transcriptional regulation of drug metabolizing enzymes such as cytochrome P450-1A1 and 1B1 CYP1A1 andCYP1B1 following ligand activation. However, evidence is emerging that AhR may have intrinsic functions that promote prostate cancer progression. Published results from our laboratory recently revealed that AhR is constitutively active in advanced prostate cancer cell lines and no longer requires ligand activation for activity. Chemical and shRNA mediated ablation of AhR signaling decreases expression of AhR responsive genes and androgen responsive genes, including PSA. In addition, treatment with an AhR antagonist reduced the growth rate of castration-resistant prostate cancer cells and restored cell responsiveness to the anti-androgen bicalutamide. The ability of AhR to regulate androgen receptor signaling in advanced prostate cancer cells identifies it as a prime target to ablate androgen receptor signaling in AA men.