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16.03.2019 | Original Paper

Role of Estrogen in Androgen-Induced Prostate Carcinogenesis in NBL Rats

Zeitschrift:
Hormones and Cancer
Autoren:
Nur Ozten, Katherine Vega, Joachim Liehr, Xi Huang, Lori Horton, Ercole L. Cavalieri, Eleanor G. Rogan, Maarten C. Bosland
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s12672-019-00360-7) contains supplementary material, which is available to authorized users.
Nur Ozten and Katherine Vega contributed equally to this work.
Joachim Liehr is deceased. This paper is dedicated to his memory.
This paper is dedicated to the memory of Joachim G. Liehr who died in 2003. He developed the notion that estrogen genotoxicity is an essential component of estrogen carcinogenesis and created a substantive body of evidence in support of this mechanism.

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Abstract

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.

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12672_2019_360_MOESM1_ESM.docx
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