Abstract 4016: The role of catechol estrogen in steroid hormone-induced prostate carcinogenesis in the Noble (NBL) rat
Authors: Bosland Maarten C. , Schlicht Michael J. 
Published: August 2018

Abstract
Results of studies with Noble (NBL) rats indicate that estrogens play a causative role in prostate carcinogenesis. In this strain, prostate adenocarcinomas develop after 6-12-mo treatment with testosterone (T), with and without estradiol-17β (E2) added. Dorsolateral prostate cancer incidence was 37% with T alone (~90 μg/d by subcutaneous [s.c.] Silastic implants), but 90-100% when E2 (~1.6 μg/d, by s.c. Silastic implants) was added to the treatment. T can be converted to E2 in the prostate by the enzyme aromatase and the catechol E2 metabolite 4-hydroxyestradiol (4OHE2) is thought to be carcinogenic. Previous short-term studies showed that 4OHE2 (5 μg/d, by s.c. slow-release implant) increased serum and prostate 4OHE2 levels 2-4-fold and increased prostatic levels of the N7-Gua and N3-Ade DNA adducts of 4OHE2. After 12-mo treatment with the same doses, 4OHE2 was slightly estrogenic, resulting in higher pituitary weights, and 4OHE2 and T+4OHE2 induced dysplastic lesions in the lateral prostate, but at a much lower incidence than with T+E2, and only cancer was found in the dorsolateral lobe, one in the anterior prostate, and one in the seminal vesicle, for a total tumor incidence of 23%. Thus, despite increasing DNA adducts and inducing dysplasia in the prostate, 4OHE2 did not induce prostate carcinomas, perhaps because it lacks strong estrogenic activity. To test whether both 4OHE2-mediated changes and estrogenic activity are required in addition to androgen for T+E2-induced prostate lesions, we used 2-fluoroestradiol (2FE2), which is estrogenic but cannot be converted to catecholestrogen. Animals were treated for 12 months with 2FE2 (~10 µg/d, by s.c. slow-release implant) or T alone or a combination of T+2FE2, 2FE2+4OHE2, or T+2FE2+4OHE2. Compared to historic controls, all 2FE2-treated rats had elevated pituitary weights and reduced prostate weights, indicative of estrogenic activity. Prostate weights were increased significantly in animals receiving T with or without 2FE2 or 4OHE2. Three of 18 animals treated with T alone developed large accessory sex gland adenocarcinomas, and a small cancer was found in the anterior prostate and the seminal vesicle in one rat each for a total cancer incidence of 28%, comparable to our previous findings with T treatment. Animals treated with T+2FE2 developed also only few prostate cancers and 2FE2+4OHE2 did not cause cancer. By contrast, 18 of 19 rats (95%) treated with T+2FE2+4OHE2 developed small adenocarcinomas in the periurethral ducts of the dorsolateral and anterior prostate; there were often multiple tumors with an average multiplicity of 2.7 tumors per rat. These findings strongly support the hypothesis that androgen and estrogen receptor-mediated action as well as catechol estrogen metabolite-induced DNA damage are all mechanistically required for a high tumor response to treatment with T+E2.
Supported by a Prevent Cancer Foundation grant.
Citation Format: Maarten C. Bosland, Michael J. Schlicht. The role of catechol estrogen in steroid hormone-induced prostate carcinogenesis in the Noble (NBL) rat [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4016.