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2-Methoxyestradiol Inhibits Prostate Tumor Development in Transgenic Adenocarcinoma of Mouse Prostate: Role of Tumor Necrosis Factor-–Stimulated Gene 6

Authors' Affiliations: Departments of ¹ Urology and ² Pharmacology, University of Texas Health Science Center, San Antonio, Texas; ³ Department of Microbiology and Kaplan Cancer Center, New York University Medical Center, New York; ⁴ Department of Pathology, University of Colorado Health Sciences Center; ⁵ Department of Radiation Biology, Colorado State University, Fort Collins; ⁶ AMC Cancer Research Center; ⁷ National Jewish Research and Medical Center, Denver, Colorado; and ⁸ Affinity Bioreagents, Golden, Colorado

Requests for reprints: Addanki P. Kumar, Department of Urology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229. Phone: 210-567-5647; Fax: 210-567-6868; E-mail: kumara3{at}uthscsa.edu.

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-–stimulated 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), antisense TSG-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.

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