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

Abstract

Estrogen receptor β (ERβ) is activated in the prostate by 5α-androstane-3β,17β-diol (3β-Adiol) where it exerts antiproliferative activity. The proliferative action of the androgen receptor is activated by 5α-dihydrotestosterone (DHT). Thus, prostate growth is governed by the balance between androgen receptor and ERβ activation. 3β-Adiol is a high-affinity ligand and agonist of ERβ and is derived from DHT by 3-keto reductase/3β-hydroxysteroid dehydrogenase enzymes. Here, we demonstrate that, when it is expressed in living cells containing an estrogen response element-luciferase reporter, 17β-hydroxysteroid dehydrogenase type 6 (17βHSD6) converts the androgen DHT to the estrogen 3β-Adiol, and this leads to activation of the ERβ reporter. This conversion of DHT occurs at concentrations that are in the physiological range of this hormone in the prostate. Immunohistochemical analysis revealed that 17βHSD6 is expressed in ERβ-positive epithelial cells of the human prostate and that, in prostate cancers of Gleason grade higher than 3, both ERβ and 17βHSD6 are undetectable. Both proteins were present in benign prostatic hyperplasia samples. These observations reveal that formation of 3β-Adiol via 17βHSD6 from DHT is an important growth regulatory pathway that is lost in prostate cancer.HSD17B6 | short-chain dehydrogenase | steroid metabolism | prereceptor regulation | intracrinology E strogen receptor β (ERβ) is a member of the nuclear receptor superfamily of transcription factors (1). ERβ is activated by its endogenous ligands estradiol-17β (E2) and 5α-androstane-3β,17β-diol (3β-Adiol). Activated ERβ is known to antagonize the proliferative actions of ERα (2-4). It has been shown that, in the prostate, 3β-Adiol is the physiological ligand of ERβ (2). This notion is supported by the fact that the intraprostatic 3β-Adiol level (10 nM) is 100-fold higher than that of E2 (0.1 nM) (5). 3β-Adiol is a metabolite of the androgen receptor (AR) agonist 5α-dihydrotestosterone (DHT).In vitro experiments using membrane preparations or purified enzymes have demonstrated that 3β-Adiol can be formed from DHT in two ways: (i) directly by 3-keto reduction of DHT to 3β-Adiol or (ii) by a two-enzyme process that entails a 3-keto reduction to 3α-Adiol followed by 3α-to 3β-hydroxysteroid epimerization.The most likely candidate enzyme for direct reduction is AKR1C1, a member of the aldo-keto reductase (AKR) family (6, 7). This cytosolic enzyme predominantly catalyzes the conversion of DHT to 3β-Adiol (8). A candidate for the first step in the twoenzyme pathway is AKR1C2, which converts DHT to 3α-Adiol (9). The mRNAs for both enzymes have been quantified in the human prostate by quantitative PCR (10); however, their cell type-specific protein expression in the prostate has not been reported.The epimerase reaction has been shown to be catalyzed by 17β-hydroxysteroid dehydrogenase type 6 (17βHSD6) (11, 12), also termed retinol dehydrogenase-like 3α-hydroxysteroid dehydrogenase (13,14). 17βHSD6 is a microsomal enzyme that belongs to the short-ch...

Estrogen receptor β sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription

“…In contrast, estrogen was unable to stimulate PHD2 expression. These data support previous studies indicating that 3β-adiol, but not estrogen, promotes an epithelial phenotype in prostate cells (9,16,17). It is worth noting, however, that the PHD1 (EGLN2) gene is estrogen inducible in breast carcinoma cells (41).…”

“…In pursuit of a functional basis for this relationship, we demonstrated that ERβ sustains an epithelial phenotype and impedes a mesenchymal transition in prostate cancer and we identified a metabolite of dihydrotestosterone, 5α-androstane-3β,17β4-diol (3β-adiol) as the specific ERβ ligand that mediates this function (9). This observation is in agreement with the recent findings that 3β-adiol is a natural ligand for ERβ in prostate (13,(15)(16)(17).…”

“…The ligand dependency of ERβ-mediated regulation of PHD2 expression was evaluated by treating both PNT1a and LNCaP cells with 3β-adiol, a natural ligand for ERβ in the prostate (9,13,(15)(16)(17). Indeed, 3β-adiol treatment caused a significant increase in PHD2 mRNA and protein expression in both cell types Author contributions: P.M., C.C., and A.M.M.…”

Estrogen receptor β exon 3-deleted mouse: The importance of non-ERE pathways in ERβ signaling

“…Aging male ERβ −/− mice developed prostate hyperplasia and prostatic intraepithelial neoplasia (PIN), a premalignant stage of adenocarcinoma (8). ERβ is also expressed in normal human prostate and in prostate cancer of Gleason grades up to 3 + 3 but its expression decreases as cancer progresses (9)(10)(11). The loss of ERβ expression during the progression from high-grade PIN to cancer suggests that ERβ may act as a tumor suppressor.…”

Variants on ESR1 and their Association with Prostate Cancer Risk: A Meta-analysis

“…Both receptors are located in the prostate glands and they have been postulated to have important effects on these glands (Harkonen et al, 2004). Many previous studies have investigated the relation between genes that are involved in the estrogen metabolism pathway and the risk of prostate carcinoma (Celhay et al, 2010;Muthusamy et al, 2011). Variants on the gene ER alpha (ESR1) have been reported to be significantly associated with the risk of other sex steroid hormone-related carcinomas, such as breast cancer (Li et al, 2010), endometrial cancer (Einarsdottir et al, 2009) and ovarian carcinoma (Doherty et al, 2010).…”