Prostatic hormonal carcinogenesis is mediated by in situ estrogen production and estrogen receptor alpha signaling.
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 alpha or ER beta signaling, ER alpha-knockout (alphaERKO) or ERbeta-knockout (betaERKO) mice were used. Prostates from betaERKO mice underwent biochemical and histological carcinogenesis similar to wild-type mice, whereas prostates from alphaERKO mice remained free of pathology. These data suggest that effective prevention of carcinogenesis will require antagonism of ER alpha but not ER beta. This mouse model provides a means to examine genetic gain and loss of function and determine the efficacy of therapeutics on prostatic carcinogenesis.
Ricke
William A
WA
Department of Urology, James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USA. william_ricke@urmc.rochester.edu
McPherson
Stephen J
SJ
Bianco
Joseph J
JJ
Cunha
Gerald R
GR
Wang
Yuzhuo
Y
Risbridger
Gail P
GP
D000818:Animals; D001141:Aromatase / Q000172:deficiency / Q000502:physiology*; D004958:Estradiol / Q000096:biosynthesis*; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011467:Prostate / Q000187:drug effects / Q000473:pathology; D011471:Prostatic Neoplasms / Q000139:chemically induced* / Q000473:pathology; D013739:Testosterone
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D013739:Testosterone; D004958:Estradiol; D001141:Aromatase