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 0.5 ng/ml 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 ng/ml. 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. 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 androgen receptor. 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.