The long term objective of this proposal is to understand the mechanisms by which the aromatic hydrocarbon receptor (AHR) disrupts androgen-induced responses in the human LNCaP (Lymph Node Cancer of the Prostate) cell line. The AHR is a ligand-inducible transcription factor that binds several environmental pollutants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD has been found to disrupt hormone-induced responses and gene expression in the reproductive systems of rodents and in human breast cancer cells lines. The goal of the proposed research is to test the hypothesis that TCDD blocks androgen-dependent cell cycle progression in LNCaP cells by interfering with the expression and activities of critical androgen-induced mediators controlling cell cycle progression. To test this hypothesis the following specific aims are proposed: (1) to determine at which phase of the cell cycle does TCDD block androgen-induced progression, and (2) to determine which cell cycle genes/proteins induced by androgens are perturbed by TCDD exposure in LNCaP cells. This research will help to define the mechanisms by which a large class of endocrine disruptors, represented by TCDD, cause adverse effects on male reproduction, fertility, and androgen-dependent cell proliferation. This work will have an important bearing in the identification of risk factors and the development of drugs to treat prostate cancer.
