2-Methoxyestradiol inhibits prostate tumor development in transgenic adenocarcinoma of mouse prostate: role of tumor necrosis factor-alpha-stimulated gene 6.
OBJECTIVE
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.


METHODS
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-alpha-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.
Garcia
Gretchen E
GE
Departments of Urology, University of Texas Health Science Center, San Antonio, Texas 78229, USA.
Wisniewski
Hans-Georg
HG
Lucia
M Scott
MS
Arevalo
Nicole
N
Slaga
Thomas J
TJ
Kraft
Susan L
SL
Strange
Robert
R
Kumar
Addanki P
AP
D000077584:2-Methoxyestradiol; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000517:prevention & control*; D000818:Animals; D015815:Cell Adhesion Molecules / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D004032:Diet; D004195:Disease Models, Animal; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000517:prevention & control*
D015815:Cell Adhesion Molecules; C072273:TNFAIP6 protein, human; C513057:Tnfaip6 protein, mouse; D004958:Estradiol; D000077584:2-Methoxyestradiol