2-Methoxyestradiol inhibits prostate tumor development in transgenic adenocarcinoma of mouse prostate: Role of tumor necrosis factor-α- stimulated gene 6

Gretchen E. Garcia, Hans Georg Wisniewski, M. Scott Lucia, Nicole Arevalo, Thomas J. Slaga, Susan L. Kraft, Robert Strange, Addanki P. Kumar

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

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-α-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. lmmunohistochemistry 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.

Original languageEnglish (US)
Pages (from-to)980-988
Number of pages9
JournalClinical Cancer Research
Volume12
Issue number3 I
DOIs
StatePublished - Feb 1 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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