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Prostatic hormonal carcinogenesis is mediated by in situ estrogen production and estrogen receptor alpha signaling

William A. Ricke^*,1, Stephen J. McPherson, Joseph J. Bianco, Gerald R. Cunha, Yuzhuo Wang and Gail P. Risbridger

^* Departments of Urology, Pathology, and Laboratory Medicine, James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York, USA;

Centre for Urological Research, Monash Institute of Medical Research, Monash University, Clayton, Australia;

Departments of Anatomy and Urology, University of California, San Francisco, California, USA; and

Department of Cancer Endocrinology and The Prostate Center, University of British Columbia, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

¹Correspondence: University of Rochester, Department of Urology, 601 Elmwood Ave., Box 656, Rochester, NY 14642, USA. E-mail: william_ricke{at}urmc.rochester.edu

It was recently demonstrated that antiestrogens prevented prostate cancer (PRCA) in men. The source of estradiol (E2) that contributes to carcinogenesis, as well as the selected estrogen receptor (ER) signaling pathway, is unknown. To evaluate estrogen’s effects in carcinogenesis, we developed a new model of PRCA utilizing testosterone and E2 to stimulate PRCA. To determine whether local in situ production of E2 affected incidence of PRCA, aromatase-knockout (ArKO) mice were evaluated. In contrast to the wild-type mice, ArKO mice had reduced incidences of PRCA, which implicates in situ production of E2 as an important determinant of PRCA. To determine whether E2-mediated responses were due to ER or ERβ signaling, ER-knockout (ERKO) or ERβ-knockout (βERKO) mice were used. Prostates from βERKO mice underwent biochemical and histological carcinogenesis similar to wild-type mice, whereas prostates from ERKO mice remained free of pathology. These data suggest that effective prevention of carcinogenesis will require antagonism of ER but not ERβ. This mouse model provides a means to examine genetic gain and loss of function and determine the efficacy of therapeutics on prostatic carcinogenesis.—Ricke, W. A., McPherson, S. J., Bianco, J. J. Cunha, G. R., Wang, Y., Risbridger, G. P. Prostatic hormonal carcinogenesis is mediated by in situ estrogen production and estrogen receptor alpha signaling.

Key Words: prostate cancer • hormone action • mouse models