EARLY CASTRATION REDUCES PROSTATIC CARCINOGENESIS IN TRANSGENIC MICE MARVIN H. ENG, LINDA G. CHARLES, BRIAN D. ROSS, CLARENCE E. CHRISP, KENNETH J. PIENTA, NORMAN M. GREENBERG, CHUN X. HSU, AND MARTIN G. SANDA ABSTRACT Objectives. To test the hypothesis that transgenic mouse models of prostate cancer could be useful for testing chemoprevention strategies by evaluating the effects of early castration on prostate carcinogenesis in TRAMP mice. Human prostate cancer, unlike other cancers, requires androgens for oncogenesis yet acquires partial androgen independence in the castrated milieu. This paradigm is the basis for an ongoing clinical trial using selective androgen 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 models of prostate carcinogenesis. Methods. Magnetic resonance imaging was used to longitudinally measure prostate growth in castrated and noncastrated TRAMP mice, and mice were prospectively examined for the onset of advanced, palpable prostate cancer. Modulation of androgen-responsive oncogene expression, as well as oncogene expression in refractory cancers, was evaluated by Western blot. Results. Early castration significantly reduced prostate tumor growth as measured by magnetic resonance imaging and improved cancer-free survival. Prevention of prostate cancer development in these mice was associated with durable suppression of androgen-responsive oncogene expression (T-antigen expression not detectable by Western blot); prostate cancers refractory to the hormonal prevention strategy demonstrated androgen-independent oncogene expression. Conclusions. These findings suggest that carcinogenesis related to androgen-responsive oncogene expres- sion 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 chemoprevention. UROLOGY 54: 1112–1119, 1999. © 1999, Elsevier Science Inc. P rostate cancer, the most common and the sec- ond deadliest cancer in American men, re- quires, unlike other cancers, androgens for onco- genesis yet acquires partial androgen indepen- dence in the castrated milieu. 1,2 This paradox has led to basic and clinical research to evaluate the possible permissive or causative roles of androgen axis abnormalities in prostate carcinogenesis and progression, as well as in targeting androgen-de- pendent pathways for the earliest to among the most recent therapeutic strategies. 1,3 Despite its significant limitations, surgical or pharmacologic castration still remains the most effective therapy for advanced prostate cancer. Complementary in- formation regarding potential preventative effects of androgen deprivation on prostate carcinogene- sis is sparse; however, clinical and cultural settings of uncorrected hypogonadism in young men have been documented, and prostate carcinoma has not been found in these subjects. 4–8 Since androgens appear to be required for prostate growth and are permissive for prostatic carcinogenesis, hormonal This study was supported by National Institutes of Health grant R29 CA71532-01 and National Institutes of Health SPORE grant 1P50 CA69568 and SPORE grant 1P50 CA58204. M. G. Sanda is the recipient of an American Cancer Society Clinical Career Development Award. From the Departments of Surgery/Urology, Radiology and Biological Chemistry, Unit for Laboratory Animal Medicine, and Medicine/Oncology, University of Michigan School of Medicine, Ann Arbor, Michigan; Department of Cell Biology, Baylor College of Medicine, Houston, Texas; and Surgery Ser- vice, Ann Arbor Veterans Affairs Medical Center, Ann Arbor, Michigan Reprint requests: Martin G. Sanda, M.D., Section of Urology, University of Michigan Hospital, 2916 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0330 Submitted: March 29, 1999, accepted (with revisions): June 8, 1999 BASIC SCIENCE © 1999, ELSEVIER SCIENCE INC. 0090-4295/99/$20.00 1112 ALL RIGHTS RESERVED PII S0090-4295(99)00297-6