Androgen like effects of heavy metals in prostate cancer

Georgetown University, Washington DC

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Abstract

DESCRIPTION (Provided by the applicant) Some of the risk factors for prostate cancer include age, endocrine status, genetic susceptibility, occupation, ethnicity, race, ultraviolet radiation, diet, and environmental factors. While the precise mechanism by which hormones affect prostate carcinogenesis is unknown, androgens appear to function as promoters of the disease. Several studies also suggest that exposure to the heavy metal cadmium may play a role in the etiology of prostate cancer. Data presented in this proposal demonstrate that environmentally relevant doses of cadmium have androgen like activity in cultured cells and in castrated animals suggesting that cadmium may also function as a promoter of prostate cancer. In LNCaP cells, the metal mimics the effects of androgens on cell growth and gene expression through a high affinity (Kd approximately 10e-10 M) interaction with the AR. Environmentally relevant doses of cadmium also mimic the effects of androgens in castrated rats and mice that is blocked by an antiandrogen suggesting that the metal activates the androgen receptor in target tissue. The goal of this proposal is to test the hypothesis that exposure to environmental doses of cadmium increases the risk of prostate cancer, in part, due to it ability to activate the AR. Three aims are proposed. Aim 1 will test whether cadmium mimics and/or enhances the effects of androgens in the N-methy-N-nitrosourea (NMU) induced prostate tumor model. This aim will also test the hypothesis that the deleterious effects of exposure to cadmium can be prevented by endocrine or other treatment strategies. The goal of aim 2 is to define the mechanism of AR activation. The studies are designed to determine whether: 1. cadmium activates the AR by a direct interaction with the receptor, such as an interaction with thiol groups in the hormone binding domain; or 2. cadmium activates the receptor by an indirect effect, such as activation of signal transduction pathways to influence the phosphorylation of the AR. Aim will determine whether the metal alters the interaction between AR and its coregulators.