Correspondence

Estrogen Receptor β in Prostate Cancer

N Engl J Med 2004; 351:2773-2774December 23, 2004

Article

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-β) had a role in this outcome. In human prostate cancer, ER-β is silenced in cancers that are not well differentiated.2 In mice, the absence of ER-β leads to failure of the prostatic epithelium to differentiate fully, whereas the epithelial cells continue to proliferate.3 If we include ER-β as a factor in the endocrine control of prostate growth, we have androgen receptors causing proliferation and secretion and ER-β 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-β in the prostate — was missing.

Investigations in our laboratories showed that a steroid, 5α-androstane-3β,17β-diol (3β-androstanediol), a metabolite of dihydrotestosterone, has all the characteristics of the natural ligand for ER-β.4 The pathway presented in Figure 1Figure 1Testosterone Pathway. is our view of the balance between androgen receptors and ER-β. Dihydrotestosterone is the fulcrum in this balance. It suggests that finasteride, by blocking the conversion of testosterone to dihydrotestosterone, inhibits the production of 3β-androstanediol, thus suppressing ER-β 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.

We suggest that finasteride be combined with an ER-β 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

4 References

1. 1

   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
   Full Text | Web of Science | Medline

2. 2

   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
   CrossRef | Web of Science | Medline

3. 3

   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
   CrossRef | Web of Science | Medline

4. 4

   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
   CrossRef | Web of Science | Medline

Citing Articles (17)

Citing Articles

1. 1

   Christoforos Thomas, Jan-Åke Gustafsson. (2011) The different roles of ER subtypes in cancer biology and therapy. Nature Reviews Cancer 11:8, 597-608
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2. 2

   Wan-Ru Chao, Khalid Amin, Yihui Shi, Peter Hobbs, Mas Tanabe, Mary Tanga, Ling Jong, Nathan Collins, Richard Peters, Keith Laderoute, Dominic Dinh, Dawn Yean, Carol Hou, Barbara Sato, Carsten Alt, Lidia Sambucetti. (2011) SR16388: a steroidal antiangiogenic agent with potent inhibitory effect on tumor growth in vivo. Angiogenesis 14:1, 1-16
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3. 3

   Stuart J. Ellem, Gail P. Risbridger. (2010) Aromatase and regulating the estrogen:androgen ratio in the prostate gland. The Journal of Steroid Biochemistry and Molecular Biology 118:4-5, 246-251
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4. 4

   Alberto Briganti. (2009) Oestrogens and Prostate Cancer: Novel Concepts about an Old Issue. European Urology 55:3, 543-545
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5. 5

   Stuart J. Ellem, Gail P. Risbridger. (2009) The Dual, Opposing Roles of Estrogen in the Prostate. Annals of the New York Academy of Sciences 1155:1, 174-186
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6. 6

   W. J. Fávaro, V. H. A. Cagnon. (2008) Immunolocalization of androgen and oestrogen receptors in the ventral lobe of rat ( Rattus norvegicus ) prostate after long-term treatment with ethanol and nicotine. International Journal of Andrology 31:6, 609-618
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7. 7

   Faysal A Yafi, Armen G Aprikian, Wassim Kassouf. (2008) Chemoprevention of prostate cancer: agents, studies and future prospects. Aging Health 4:5, 469-479
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8. 8

   A-H Karypidis, M Olsson, S-O Andersson, A Rane, L Ekström. (2008) Deletion polymorphism of the UGT2B17 gene is associated with increased risk for prostate cancer and correlated to gene expression in the prostate. The Pharmacogenomics Journal 8:2, 147-151
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9. 9

   Alberto Briganti, Felix K.-H. Chun, Nazareno Suardi, Andrea Gallina, Jochen Walz, Markus Graefen, Shahrokh Shariat, Andreas Ebersdobler, Patrizio Rigatti, Paul Perrotte, Fred Saad, Francesco Montorsi, Hartwig Huland, Pierre I. Karakiewicz. (2007) Prostate volume and adverse prostate cancer features: Fact not artifact. European Journal of Cancer 43:18, 2669-2677
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10. 10

    B.J. Schmitz-Dräger, C. Fischer, E. Bismarck, H.J. Dörsam, G. Lümmen. (2007) Das „Prostate Cancer Prevention Trial“ (PCPT). Der Urologe 46:10, 1364-1370
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11. 11

    Mats Olsson, Ove Gustafsson, Cristine Skogastierna, Anna Tolf, Barbara Du Rietz, Robert Morfin, Anders Rane, Lena Ekström. (2007) Regulation and expression of human CYP7B1 in prostate: Overexpression of CYP7B1 during progression of prostatic adenocarcinoma. The Prostate 67:13, 1439-1446
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12. 12

    M A Goetzl, P J VanVeldhuizen, J B Thrasher. (2007) Effects of soy phytoestrogens on the prostate. Prostate Cancer and Prostatic Diseases 10:3, 216-223
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13. 13

    Janet K. Hess-Wilson, Siobhan L. Webb, Hannah K. Daly, Yuet-Kin Leung, Joanne Boldison, Clay E.S. Comstock, Maureen A. Sartor, Shuk-Mei Ho, Karen E. Knudsen. (2007) Unique Bisphenol A Transcriptome in Prostate Cancer: Novel Effects on ERβ Expression That Correspond to Androgen Receptor Mutation Status. Environmental Health Perspectives 115:11, 1646-1653
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14. 14

    Stuart J. Ellem, Gail P. Risbridger. (2007) Treating prostate cancer: a rationale for targeting local oestrogens. Nature Reviews Cancer 7:8, 621-627
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15. 15

    Maria Hedelin, Katarina Augustsson Bälter, Ellen T. Chang, Rino Bellocco, Åsa Klint, Jan-Erik Johansson, Fredrik Wiklund, Camilla Thellenberg-Karlsson, Hans-Olov Adami, Henrik Grönberg. (2006) Dietary intake of phytoestrogens, estrogen receptor-beta polymorphisms and the risk of prostate cancer. The Prostate 66:14, 1512-1520
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16. 16

    ROBERT (FRANK) A. GARDINER, DAVID L. NICOL, HEATHER J. GREEN, KEN I PAKENHAM. (2006) SIDE-EFFECTS OF TREATMENTS FOR LOCALLY ADVANCED PROSTATE CANCER. BJU International 98:1, 229-230
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17. 17

    Mischel G. Neill, Neil E. Fleshner. (2006) An update on chemoprevention strategies in prostate cancer for 2006. Current Opinion in Urology 16:3, 132-137
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