Disruption of cellular zinc homeostasis in transgenic adenocarcinoma mouse prostate (TRAMP) mice leads to an early onset of prostate cancer and metastasis

Abstract

Decrease of cellular zinc in the epithelium of the prostate has been implicated in the development of prostate cancer. To investigate whether ZnT7, a zinc transporter involved in intracellular zinc accumulation, played a role in prostate cancer development, we generated and characterized a transgenic adenocarcinoma mouse prostate (TRAMP) model with a Znt7-null genetic background. Four week old male TRAMP mice (TRAMP/Znt7−/− and TRAMP/Znt7+/+) were fed a semi-purified diet containing 15 mg zinc/kg diet for 2–24 weeks. Mice were euthanized at 6, 8, 16, and 28 weeks for histopathological analysis of the prostates and for the presence of prostate tumors and metastasis. At 6 and 8 weeks of age, TRAMP/Znt7−/− mice displayed higher frequencies of low grade prostatic intraepithelial neoplasia (PIN) and high grade PIN, respectively, in the prostates compared to the age-matched TRAMP/Znt7−/− mice. At 16 weeks of age, 33% TRAMP/Znt7−/− mice had prostate tumors and one half of the mice with prostate tumors had tumor metastasized to the draining lymph nodes while no prostate tumor was detected in the control TRAMP mice. By 28 weeks, 67% TRAMP/Znt7−/− mice developed prostate tumors while only 22% control TRAMP mice had prostate tumors. Furthermore, apoptosis was reduced in the prostates of TRAMP/Znt7−/− mice. In conclusion, disruption of cellular zinc homeostasis caused by the Znt7 knockout leads to an early onset of prostate cancer and metastasis in TRAMP mice. This work was supported by the United States Department of Agriculture, ARS projects 5306-515-30-014-00D and 5306-515-20-007-00D.