Early castration reduces prostatic carcinogenesis in transgenic mice

Objectives. To test the hypothesis that transgenic mouse models of prostate cancer could be useful for testing chemoprevention strategies by evaluatin g the effects of early castration on prostate carcinogenesis in TRAMP mice, Human prostate cancer, unlike other cancers, requires androgens for oncoge nesis yet acquires partial androgen independence in the castrated milieu. T his paradigm is the basis for an ongoing clinical trial using selective and rogen deprivation for prostate cancer chemoprevention. However, preclinical correlates for hormonal prevention or other chemoprevention strategies of prostate cancer have not previously been demonstrated in autochthonous mode ls of prostate carcinogenesis. Methods. Magnetic resonance imaging was used to longitudinally measure pros tate growth in castrated and noncastrated TRAMP mice, and mice were prospec tively examined for the onset of advanced, palpable prostate cancer. Modula tion of androgen-responsive oncogene expression, as well as oncogene expres sion in refractory cancers, was evaluated by Western blot. Results. Early castration significantly reduced prostate tumor growth as me asured by magnetic resonance imaging and improved cancer-free survival. Pre vention of prostate cancer development in these mice was associated with du rable suppression of androgen-responsive oncogene expression (T-antigen exp ression not detectable by Western blot); prostate cancers refractory to the hormonal prevention strategy demonstrated androgen-independent oncogene ex pression. Conclusions, These findings suggest that carcinogenesis related to androgen -responsive oncogene expression can be prevented in some cases by hormonal manipulation and that transgenic TRAMP mice are useful for the preclinical evaluation of hormonal and possibly other strategies of prostate cancer che moprevention. (C) 1999, Elsevier Science Inc.