Fatty acid synthase: An early molecular marker of progression of prostaticadenocarcinoma to androgen independence

Purpose: Changes in fatty acid synthase levels were investigated in the CWR 22 xenograft model of prostatic adenocarcinoma after castration and during progression to androgen independence. Materials and Methods: Male nude mice with CWR22 tumors were castrated and sacrificed 3, 7, 21, 28 or 42 days after castration. Some mice received tes tosterone replenishment 21 days after castration and were sacrificed 7 days later. In addition, other castrates were maintained for 7 to 10 months to allow tumors to relapse to androgen independence. Fatty acid synthase was m easured by immunohistochemical study and Western blot analysis. Results: Fatty acid synthase decreased rapidly after castration and after 2 8 to 42 days it was 5% to 10% of the level in tumors of intact controls. Te mporal changes in fatty acid synthase after castration were associated with decreased proliferative potential and increased levels of the cyclin depen dent kinase inhibitor p27Kip-1. Testosterone treatment of castrates at 21 t o 28 days after castration increased fatty acid synthase expression to the level in tumors of intact controls. Tumors of long-term castrates with post -castration androgen independent growth had increased fatty acid synthase, as did small focal areas of androgen independent proliferation in tumors th at had not increased in size by 7 to 10 months. In relapsed CWR22 tumors an d in focal areas of androgen independent proliferation in nonrelapsed CWR22 tumors increased fatty acid synthase was associated spatially with increas ed proliferation and decreased p27Kip-1. Conclusions: Fatty acid synthase in CWR22 tumors depends initially on testo sterone and it is associated with androgen mediated proliferation. Furtherm ore, increased fatty acid synthase levels associated with androgen independ ent proliferation may represent an early event in the development of the an drogen independent phenotype.