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Purpose: 2-Methoxyestradiol, an estrogenic metabolite, is in clinical trials for the treatment of hormone-refractory prostate cancer. However, neither the chemopreventive role nor the mechanism of 2-methoxyestradiol^induced biological activities is fully understood. Experimental Design: Eight-and 24-week-old transgenic adenocarcinoma of mouse prostate (TRAMP) mice were fed a diet containing 50 mg 2-methoxyestradiol/kg body weight for 16 and 8 weeks, respectively. Chemopreventive efficacy was evaluated by magnetic resonance imaging, determining the prostate-seminal vesicle complex volume and histologic analysis of prostate tumor or tissue. Tumor invasion assays were used to show the role of tumor necrosis factor-aŝ timulated gene (TSG-6), a 2-methoxyestradiol^up-regulated gene identified by DNA array analysis. Expression of TSG-6 was analyzed in a human tissue array containing different grades of prostate tumors. Results: Dietary administration of 2-methoxyestradiol prevented the development of preneoplastic lesions independent of progression stage. TSG-6 was low or undetectable in prostate cancer cells (LNCaP, PC-3, and DU145) and TRAMP tumors but up-regulated in response to 2-methoxyestradiol. Immunohistochemistry of the human prostate tumor array showed a decrease in TSG-6^positive cells with increasing grade relative to normal prostate (P = 0.0001). Although overexpression of TSG-6 inhibited invasion of androgen-independent cells (P = 0.007), antisenseTSG-6 reversed this effect. Conclusions: To the best of our knowledge, this is the first report showing the potential of 2-methoxyestradiol as a chemopreventive agent. We have also identified TSG-6 as a potential marker that could be used for early diagnosis and prognosis of cancerous or precancerous lesions.Prostate cancer is the second leading cause of cancer-related deaths in men and affects one man in nine over the age of 65 years (1). Although it is not clear whether appearance of prostatic intraepithelial neoplasia predicts the appearance of prostate cancer in men, preneoplastic lesions have been found in young men in the twenties and are fairly common in men in fifties (2). However, clinically detectable prostate cancer does not generally manifest until the age of 60 or 70 years. In addition, the occurrence of precancerous lesions is more prevalent (f1 in 3 men) than the incidence of carcinoma (f1 in 9 men; ref.3). It is of utmost importance at this juncture to develop strategies for the prevention of early-stage prostate cancer to ensure quality of life for elderly men. Furthermore, although prostate-specific antigen is used as a marker to detect prostate cancer, its reliability has been found to be questionable in some cases (4, 5). Also presently, there is no molecular marker that can be used to detect a precancerous state or identify which premalignant lesions will develop into invasive prostate cancer.Recent results from different groups, including ours, have shown that 2-methoxyestradiol inhibits the growth of androgen-responsive and androg...

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