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Prostatic hormonal carcinogenesis is mediated by in situ estrogen production and estrogen receptor alpha signaling
Author(s) -
Ricke William A.,
McPherson Stephen J.,
Bianco Joseph J.,
Cunha Gerald R.,
Wang Yuzhuo,
Risbridger Gail P.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-9526com
Subject(s) - carcinogenesis , estrogen , aromatase , estrogen receptor , medicine , endocrinology , estrogen receptor alpha , knockout mouse , cancer research , prostate cancer , biology , prostate , cancer , receptor , breast cancer
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 wildtype mice, ArKO mice had reduced incidences of PRCA, which imμlicates in situ production of E2 as an important determinant of PRCA. To determine whether E2‐mediated responses were due to ERα or ERβ signaling, ERα‐knockout (αERKO) or ERβ‐knockout (βERKO) mice were used. Prostates from βERKO mice underwent biochemical and histological carcinogenesis similar to wild‐type mice, whereas prostates from αERKO mice remained free of pathology. These data suggest that effective prevention of carcinogenesis will require antagonism of ERα 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. FASEB J . 22, 1512–1520 (2008)