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(The FASEB Journal. 2009;23:1285-1286.)
© 2009 FASEB

Response by William A. Ricke,2

William A. Ricke2

2 Correspondence: Departments of Urology, Pathology and Laboratory Medicine, James P. Wilmot Cancer Center, 601 Elmwood Ave., Box 656, Rochester, NY 14642, USA. E-mail: william_ricke{at}urmc.rochester.edu

The prostate is commonly thought of as an androgen target tissue. However, estrogens also affect prostate biology (1 2 3) . In regard to estrogens and the prostate, the prostate gland contains the P450 enzyme, aromatase (4) , which converts testosterone to estradiol-17β (E2), which signals primarily through estrogen receptor (ER)-{alpha} and -β via classical and genomic methods. Therefore, within the prostate, androgens may act as an androgen via the androgen receptor pathway as well as an estrogen, acting via ER pathways. In this regard, we have recently implicated in situ production of E2 and ER-{alpha} as mediators of prostatic carcinogenesis (5) . These observations are pertinent to clinical sciences and the prevention of prostatic carcinogenesis, as well as to the understanding of the basic mechanism(s) of estrogen hormone action during carcinogenesis.

Preclinical studies have demonstrated that selective ER modulators (SERMs) prevent prostate cancer (PRCA) progression (6 , 7) . Moreover, it has been determined recently that use of SERMs prevents PRCA progression in men (8) . These findings are significant, as SERMs have few side-effects and therefore, may provide a reasonable therapeutic means in the prevention of PRCA progression. It is unknown by which mechanism(s) SERMs prevent PRCA. A better understanding of how estrogens elicit carcinogenesis and which ERs are necessary for carcinogenesis will undoubtedly lead to better clinical treatments.

Demethylation of the aromatase gene promoter leading to increased aromatase activity followed by E2 generation and E2 binding to ERs to form ER-{alpha} homo- or heterodimers may be key steps in PRCA progression, as hypothesized by Friedman (see communication above). On the other hand, the idea that other estrogens and/or ERs are playing important roles in carcinogenesis is similarly plausible. For example, within the body, there are many types of estrogens that elicit estrogenic signaling, including estrone, hydroxycholesterol, and environmental estrogens (e.g. bisphenol-A) (9 10 11) . Furthermore, although classical action of ER-{alpha} and ER-β is a likely mediator of estrogens, other ERs, classical and nonclassical, have been reported (12 13 14 15) . Until other key estrogen sources and ERs are identified and implicated in the prostate, the mechanism(s) associated with estrogenic induction of carcinogenesis are more speculation than fact. Further research is needed to help determine the role of estrogens in prostatic carcinogenesis.

REFERENCES

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  2. Omoto, Y., Imamov, O., Warner, M., Gustafsson, J. A. (2005) Estrogen receptor {alpha} and imprinting of the neonatal mouse ventral prostate by estrogen. Proc. Natl. Acad. Sci. USA 102,1484-1489
  3. Risbridger, G., Wang, H., Young, P., Kurita, T., Wang, Y. Z., Lubahn, D., Gustafsson, J. A., Cunha, G. (2001) Evidence that epithelial and mesenchymal estrogen receptor-{alpha} mediates effects of estrogen on prostatic epithelium. Dev. Biol. 229,432-442
  4. Ellem, S. J., Schmitt, J. F., Pedersen, J. S., Frydenberg, M., Risbridger, G. P. (2004) Local aromatase expression in human prostate is altered in malignancy. J. Clin. Endocrinol. Metab. 89,2434-2441
  5. Ricke, W. A., McPherson, S. J., Bianco, J. J., Cunha, G. R., Wang, Y., Risbridger, G. P. (2008) Prostatic hormonal carcinogenesis is mediated by in situ estrogen production and estrogen receptor {alpha} signaling. FASEB J. 22,1512-1520
  6. Raghow, S., Hooshdaran, M. Z., Katiyar, S., Steiner, M. S. (2002) Toremifene prevents prostate cancer in the transgenic adenocarcinoma of mouse prostate model. Cancer Res. 62,1370-1376
  7. Zeng, Y., Yokohira, M., Saoo, K., Takeuchi, H., Chen, Y., Yamakawa, K., Matsuda, Y., Kakehi, Y., Imaida, K. (2005) Inhibition of prostate carcinogenesis in probasin/SV40 T antigen transgenic rats by raloxifene, an antiestrogen with anti-androgen action, but not nimesulide, a selective cyclooxygenase-2 inhibitor. Carcinogenesis 26,1109-1116
  8. Price, D., Stein, B., Sieber, P., Tutrone, R., Bailen, J., Goluboff, E., Burzon, D., Bostwick, D., Steiner, M. (2006) Toremifene for the prevention of prostate cancer in men with high grade prostatic intraepithelial neoplasia: results of a double-blind, placebo controlled, phase IIB clinical trial. J. Urol. 176,965-970
  9. Belanger, A., Candas, B., Dupont, A., Cusan, L., Diamond, P., Gomez, J. L., Labrie, F. (1994) Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men. J. Clin. Endocrinol. Metab. 79,1086-1090
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  11. Lakind, J. S., Naiman, D. Q. (2008) Bisphenol A (BPA) daily intakes in the United States: estimates from the 2003–2004 NHANES urinary BPA data. J. Expo. Sci. Environ. Epidemiol. 18,608-615
  12. Zhang, G., Liu, X., Farkas, A. M., Parwani, A. V., Lathrop, K. L., Lenzner, D., Land, S. R., Srinivas, H. (2009) Estrogen receptor β functions through nongenomic mechanisms in lung cancer cells. Mol. Endocrinol. 23,146-156
  13. Lee, L. M., Cao, J., Deng, H., Chen, P., Gatalica, Z., Wang, Z. Y. (2008) ER-{alpha}36, a novel variant of ER-{alpha}, is expressed in ER-positive and -negative human breast carcinomas. Anticancer Res. 28,479-483
  14. Pedram, A., Razandi, M., Wallace, D. C., Levin, E. R. (2006) Functional estrogen receptors in the mitochondria of breast cancer cells. Mol. Biol. Cell 17,2125-2137
  15. Revankar, C. M., Cimino, D. F., Sklar, L. A., Arterburn, J. B., Prossnitz, E. R. (2005) A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 307,1625-1630

Related Article

Prostatic hormonal carcinogenesis is mediated by in situ estrogen production and estrogen receptor alpha signaling
William A. Ricke, Stephen J. McPherson, Joseph J. Bianco, Gerald R. Cunha, Yuzhuo Wang, and Gail P. Risbridger
FASEB J 2008 22: 1512-1520. [Abstract] [Full Text] [PDF]




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