ANDROGEN-INDEPENDENT PROSTATE-CANCER PROGRESSION IN THE TRAMP MODEL

We previously established the autochthonous transgenic adenocarcinoma mouse prostate (TRAMP) model to facilitate characterization of molecul ar mechanisms involved in the initiation and progression of prostate c ancer, TRAMP mice display high grade prostatic intraepithelial neoplas ia or well-differentiated prostate cancer by 10-12 weeks of age, To te st the hypothesis that molecular events leading to androgen independen ce and metastasis can occur early in the natural history of prostate c ancer yet remain silent until selective pressures such as androgen dep rivation are applied, we have examined the consequences of castration on the initiation and progression to metastatic prostate cancer in TRA MP mice. Cohorts were castrated at 12 weeks of age and sacrificed at 1 8 (T12/18) or 24 (T12/24) weeks of age, and the development of primary cancer and metastatic disease was compared to noncastrated (T18 and T 24) controls, Median T12/18 and T12/24 genitourinary (GU) weight was s ignificantly Less than T18 and T24, respectively, In addition, T12/24 GU weight was significantly greater than T12/18, Histological prostate tumors developed in 3 of 7 T12/18 and 8 of 10 T12/24 mice, All tumors that developed in castrated mice were poorly differentiated in contra st to 27% in noncastrated controls, Although castration significantly decreased GU tumor burden, overall progression to poorly differentiate d and metastatic disease was not ultimately delayed, These results dem onstrate that prostate cancer in the TRAMP model is heterogeneous with respect to androgen dependence as early as 12 weeks of age; therefore , early androgen ablation may have a variable impact on progression in an individual mouse. Further analysis of this prostate cancer model t o identify specific molecular mechanisms that determine androgen sensi tivity may facilitate future initiation of appropriate individualized hormonal therapy for the management of human prostate cancer.