TY - JOUR
T1 - 2-Methoxyestradiol inhibits prostate tumor development in transgenic adenocarcinoma of mouse prostate
T2 - Role of tumor necrosis factor-α- stimulated gene 6
AU - Garcia, Gretchen E.
AU - Wisniewski, Hans Georg
AU - Lucia, M. Scott
AU - Arevalo, Nicole
AU - Slaga, Thomas J.
AU - Kraft, Susan L.
AU - Strange, Robert
AU - Kumar, Addanki P.
PY - 2006/2/1
Y1 - 2006/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=32944476631&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=32944476631&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-05-2068
DO - 10.1158/1078-0432.CCR-05-2068
M3 - Article
C2 - 16467113
AN - SCOPUS:32944476631
SN - 1078-0432
VL - 12
SP - 980
EP - 988
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 3 I
ER -