Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer

Estrogen receptor beta (ER beta) is activated in the prostate by 5 alpha-androstane-3 beta, 17 beta-diol (3 beta-Adiol) where it exerts antiproliferative activity. The proliferative action of the androgen receptor is activated by 5 alpha-dihydrotestosterone (DHT). Thus, prostate growth is governed by the balance between androgen receptor and ER beta activation. 3 beta-Adiol is a high-affinity ligand and agonist of ER beta and is derived from DHT by 3-keto reductase/3 beta-hydroxysteroid dehydrogenase enzymes. Here, we demonstrate that, when it is expressed in living cells containing an estrogen response element-luciferase reporter, 17 beta-hydroxysteroid dehydrogenase type 6 (17 beta HSD6) converts the androgen DHT to the estrogen 3 beta-Adiol, and this leads to activation of the ER beta reporter. This conversion of DHT occurs at concentrations that are in the physiological range of this hormone in the prostate. Immunohistochemical analysis revealed that 17 beta HSD6 is expressed in ER beta-positive epithelial cells of the human prostate and that, in prostate cancers of Gleason grade higher than 3, both ER beta and 17 beta HSD6 are undetectable. Both proteins were present in benign prostatic hyperplasia samples. These observations reveal that formation of 3 beta-Adiol via 17 beta HSD6 from DHT is an important growth regulatory pathway that is lost in prostate cancer.