Hormonal and genotoxic estrogen‐androgen carcinogenesis in the NBL rat prostate: A role for aromatase

Abstract

Background Androgens are generally thought to cause prostate cancer, but the data from animal studies suggest that they must be aromatized to estrogen and act in concert with genotoxic estrogen metabolites. The objective of this study was to determine whether treatment with testosterone (T) combined with a nonestrogenic estrogen metabolite and a nongenotoxic estrogenic compound would all be necessary and sufficient for the induction of a high incidence of prostate cancer in the susceptible NBL rat strain. Methods NBL rats were treated with low‐dose testosterone via slow‐release Silastic implants and with the marginally estrogenic genotoxic catechol estrogen 4‐hydroxyestradiol (4OH‐E2) and the nongenotoxic estrogen 2‐fluoroestradiol (2F‐E2) and in one experiment the aromatase inhibitor letrozole via custom‐made slow‐release pellets. Animals were euthanized 52 weeks after implantation and their pituitaries and prostate complexes weighed and fixed in formalin. Hematoxylin and eosin (H&E)‐stained step sections were prepared and examined microscopically for proliferative lesions. Results Animals treated with 2F‐E2, with or without the other compounds, had enlarged pituitaries demonstrating its estrogenicity. Animals treated with T, with or without the other compounds, had enlarged prostates consistent with its androgenicity. Rats treated with T plus 2F‐E2 and 4OH‐E2 developed a high incidence of prostatic cancer (89%), while, surprisingly, rats treated with T plus only 2F‐E2 also had a high incidence of prostate cancer (95%) contradicting our initial hypothesis. To test whether the formation of E2 from T by aromatase could lead to estrogen genotoxicity and prostate carcinogenesis we then rats treated with T and 2F‐E2 also with letrozole and found that it reduced prostate cancer incidence by about 50%. Conclusions These findings indicate that long‐term treatment with a nongenotoxic estrogen (2F‐E2) and T as well as uninhibited prostatic aromatase activity generating genotoxic E2 are all required for induction of a high incidence of prostatic adenocarcinomas in NBL rats. These and previous data indicate that androgen receptor‐mediated action, estrogen receptor mediation, and estrogen genotoxicity are all required and sufficient for hormonal carcinogenesis in the NBL rat prostate. Interference with the estrogen genotoxicity is a potential approach to prostate cancer chemoprevention.