Role of Estrogen in Androgen-Induced Prostate Carcinogenesis in NBL Rats
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Androgens are thought to cause prostate cancer, but the underlying mechanisms are unclear. Data from animal studies suggest that for androgens to cause prostate cancer, they must be aromatized to estrogen and act in concert with estrogen metabolites. We tested the hypothesis that androgen-receptor and estrogen receptor-mediated effects of androgen and estrogen are necessary, as well as genotoxicity of estrogen metabolites. NBL rats were treated with androgenic and estrogenic compounds for 16–75 weeks through slow-release silastic implants or pellets. Testosterone alone induced cancer in the prostate of 37% of rats. 5α-Dihydrotestosterone, which cannot be converted to estradiol or testosterone, did not cause a significant prostate cancer incidence (4%). Addition of estradiol to 5α-dihydrotestosterone treatment did not markedly enhance prostate cancer incidence (14%), unlike adding estradiol to testosterone treatment which induced a 100% tumor incidence. Testosterone plus estradiol treatment induced a DNA adduct detectable by 32P-postlabeling, oxidative DNA damage (8-hydroxyguanosine), and lipid peroxidation at the site within the prostate where this treatment causes cancers, preceding later cancer formation. The non-estrogenic 4-hydroxy metabolite of estradiol, when combined with testosterone, induced prostatic dysplasia within 16 weeks and, after long-term treatment, a very low incidence of prostate cancer (21%). When an estrogen that cannot be hydroxylated (2-fluoroestradiol) was added to this combined treatment with testosterone and 4-hydroxyestradiol, dysplasia frequency after 16 weeks was doubled. These results strongly support the hypothesis, but additional definitive studies are needed which may identify new targets to interfere with these mechanisms that are clinically feasible in humans.
KeywordsProstate cancer Estrogen Androgen Hormonal carcinogenesis
The authors acknowledge dedicated contributions of the staff of the animal and histology facilities of the Department of Environmental Medicine at the Nelson Institute in Tuxedo, NY.
This work was supported in part by the National Institutes of Health (CA159385, CA104334, CA75293, and CA48084 to MCB, CA104334-S1, to KV) and the Prevent Cancer Foundation (to MCB).
Compliance with Ethical Standards
The animal experiments described in this paper were reviewed and approved by the NYU School of Medicine Institutional Animal Care and Use Committee and all applicable national and institutional guidelines for the care and use of animals were followed.
Conflict of Interest
The authors declare that they have no conflicts of interest.
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