Estrogen Receptor in Prostate Cancer
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《新英格兰医药杂志》
To the Editor: In the Prostate Cancer Prevention Trial,1 more than 18,000 healthy volunteers were randomly assigned to receive either finasteride (5 mg daily) or placebo. The incidence of prostate cancer in the finasteride group was 18.4 percent, as compared with 24.4 percent in the placebo group. A bigger surprise was that the incidence of tumors with a Gleason grade of 7, 8, 9, or 10 was higher in the finasteride group than in the placebo group (37.0 percent vs. 22.2 percent, P<0.001), meaning that there were more cases of aggressive cancer with finasteride than there were with placebo.1
We would like to suggest that the second estrogen receptor (ER-) had a role in this outcome. In human prostate cancer, ER- is silenced in cancers that are not well differentiated.2 In mice, the absence of ER- leads to failure of the prostatic epithelium to differentiate fully, whereas the epithelial cells continue to proliferate.3 If we include ER- as a factor in the endocrine control of prostate growth, we have androgen receptors causing proliferation and secretion and ER- suppressing proliferation and promoting differentiation. Since proliferation and differentiation oppose each other, cellular homeostasis must be the result of a dynamic balance. Until recently, a key component of this balance — the natural ligand for ER- in the prostate — was missing.
Investigations in our laboratories showed that a steroid, 5-androstane-3,17-diol (3-androstanediol), a metabolite of dihydrotestosterone, has all the characteristics of the natural ligand for ER-.4 The pathway presented in Figure 1 is our view of the balance between androgen receptors and ER-. Dihydrotestosterone is the fulcrum in this balance. It suggests that finasteride, by blocking the conversion of testosterone to dihydrotestosterone, inhibits the production of 3-androstanediol, thus suppressing ER- and preventing the differentiation of epithelium. This mechanism could account for the higher incidence of poorly differentiated tumors in the finasteride group in the Prostate Cancer Prevention Trial.
Figure 1. Testosterone Pathway.
5-R denotes 5-reductase, 3-HSD 3-hydroxysteroid dehydrogenase, and CYP7B1 oxysterol 7 -hydroxylase.
We suggest that finasteride be combined with an ER- agonist in future studies of chemoprevention of prostate cancer.
Otabek Imamov, M.D.
Karolinska Institute
14186 Huddinge, Sweden
Nikolay A. Lopatkin, M.D., Ph.D.
Moscow Institute of Urology
105425 Moscow, Russia
Jan-Ake Gustafsson, M.D., Ph.D.
Karolinska Institute
14186 Huddinge, Sweden
jan-ake.gustafsson@mednut.ki.se
References
Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:215-224.
Zhu X, Leav I, Leung YK, et al. Dynamic regulation of estrogen receptor-beta expression by DNA methylation during prostate cancer development and metastasis. Am J Pathol 2004;164:2003-2012.
Imamov O, Morani A, Shim GJ, et al. Estrogen receptor beta regulates epithelial cellular differentiation in the mouse ventral prostate. Proc Natl Acad Sci U S A 2004;101:9375-9380.
Weihua Z, Lathe R, Warner M, Gustafsson JA. An endocrine pathway in the prostate, ERbeta, AR, 5alpha-androstane-3beta,17beta-diol, and CYP7B1, regulates prostate growth. Proc Natl Acad Sci U S A 2002;99:13589-13594.
We would like to suggest that the second estrogen receptor (ER-) had a role in this outcome. In human prostate cancer, ER- is silenced in cancers that are not well differentiated.2 In mice, the absence of ER- leads to failure of the prostatic epithelium to differentiate fully, whereas the epithelial cells continue to proliferate.3 If we include ER- as a factor in the endocrine control of prostate growth, we have androgen receptors causing proliferation and secretion and ER- suppressing proliferation and promoting differentiation. Since proliferation and differentiation oppose each other, cellular homeostasis must be the result of a dynamic balance. Until recently, a key component of this balance — the natural ligand for ER- in the prostate — was missing.
Investigations in our laboratories showed that a steroid, 5-androstane-3,17-diol (3-androstanediol), a metabolite of dihydrotestosterone, has all the characteristics of the natural ligand for ER-.4 The pathway presented in Figure 1 is our view of the balance between androgen receptors and ER-. Dihydrotestosterone is the fulcrum in this balance. It suggests that finasteride, by blocking the conversion of testosterone to dihydrotestosterone, inhibits the production of 3-androstanediol, thus suppressing ER- and preventing the differentiation of epithelium. This mechanism could account for the higher incidence of poorly differentiated tumors in the finasteride group in the Prostate Cancer Prevention Trial.
Figure 1. Testosterone Pathway.
5-R denotes 5-reductase, 3-HSD 3-hydroxysteroid dehydrogenase, and CYP7B1 oxysterol 7 -hydroxylase.
We suggest that finasteride be combined with an ER- agonist in future studies of chemoprevention of prostate cancer.
Otabek Imamov, M.D.
Karolinska Institute
14186 Huddinge, Sweden
Nikolay A. Lopatkin, M.D., Ph.D.
Moscow Institute of Urology
105425 Moscow, Russia
Jan-Ake Gustafsson, M.D., Ph.D.
Karolinska Institute
14186 Huddinge, Sweden
jan-ake.gustafsson@mednut.ki.se
References
Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:215-224.
Zhu X, Leav I, Leung YK, et al. Dynamic regulation of estrogen receptor-beta expression by DNA methylation during prostate cancer development and metastasis. Am J Pathol 2004;164:2003-2012.
Imamov O, Morani A, Shim GJ, et al. Estrogen receptor beta regulates epithelial cellular differentiation in the mouse ventral prostate. Proc Natl Acad Sci U S A 2004;101:9375-9380.
Weihua Z, Lathe R, Warner M, Gustafsson JA. An endocrine pathway in the prostate, ERbeta, AR, 5alpha-androstane-3beta,17beta-diol, and CYP7B1, regulates prostate growth. Proc Natl Acad Sci U S A 2002;99:13589-13594.