A role for estrogen receptor β in the regulation of growth of the ventral prostate

Abstract

In normal rats and mice, immunostaining with specific antibodies revealed that nuclei of most prostatic epithelial cells harbor estrogen receptor ␤ (ER␤). In rat ventral prostate, 530-and 549-aa isoforms of the receptor were identified. These sediment in the 4S region of low-salt sucrose gradients, indicating that prostatic ER␤ does not contain the same protein chaperones that are associated with ER␣. Estradiol (E2) binding and ER␤ immunoreactivity coincide on the gradient, with no indication of ER␣. In prostates from mice in which the ER␤ gene has been inactivated (BERKO), androgen receptor (AR) levels are elevated, and the tissue contains multiple hyperplastic foci. Most epithelial cells express the proliferation antigen Ki-67. In contrast, prostatic epithelium from wild-type littermates is single layered with no hyperplasia, and very few cells express Ki-67. Rat ventral prostate contains an estrogenic component, which comigrates on HPLC with the testosterone metabolite 5␣-androstane-3␤,17␤-diol (3␤Adiol). This compound, which competes with E 2 for binding to ER␤ and elicits an estrogenic response in the aorta but not in the pituitary, decreases the AR content in prostates of wild-type mice but does not affect the elevated levels seen in ER␤ knockout (BERKO) mice. Thus ER␤, probably as a complex with 3␤Adiol, is involved in regulating the AR content of the rodent prostate and in restraining epithelial growth. These findings suggest that ligands specific for ER␤ may be useful in the prevention and͞or clinical management of prostatic hyperplasia and neoplasia. E pidemiological and experimental studies indicate that estrogenic hormones are involved in both the induction and prevention of prostatic cancer (1-7), but their precise role is not well understood. Excessive exposure to estrogens during critical stages of development or long-term treatment of adult animals with estrogens or androgens leads to prostatic neoplasia (8, 9). In apparent contrast, diets rich in phytoestrogens, particularly soy products, are associated with a low risk of prostate cancer (10-12) and have chemopreventive properties in experimental tumor models (12, 13). Some of these conflicting observations may be explained by the fact that there are two distinct estrogen receptors, ER␣ and ER␤, which have unique and sometimes opposing roles (14). For example, recent studies have demonstrated that, in the rodent uterus, ER␤ acts to restrain the stimulatory action of ER␣ (15).Early studies, using both ligand-binding and immunochemical techniques, detected two types of estrogen-binding substances in human prostate (16), one of which is the classical estrogen receptor now known as ER␣. Low levels of this receptor are present in the stroma of rodent prostates, but none is detectable in the epithelium (17, 18). Because of this difference in the levels of this receptor, it was proposed that the effects of estrogen on the epithelium are indirect via an initial interaction with the stroma (18). But after the discovery of ER␤ in rat prostatic epithelium ...

Differential expression of steroid receptors in prostate tissues before and after radiation therapy for prostatic adenocarcinoma

“…The function of ER-b is not completely understood and it has been suggested that the receptor, acting through estrogens, may protect normal prostate epithelial from undergoing unscheduled cell proliferation, neoplastic transformation and from oxidative injuries. 8,13,22,[28][29][30] Even though the expression of ER-b in early prostate carcinoma and also in high grade prostatic intraepithelial neoplasia is decreased compared to normal prostatic epithelium, and some authors have found in cell line studies that its forced expression inhibits invasion and proliferation and triggers apoptosis, 31 its expression in PCa cells seems to be associated with cell survival, is highly expressed in metastatic prostate carcinoma and in our previous study was also associated with higher Gleason grades. 8,15,[32][33][34] Of note, ER-b, via an AP1-like antioxidant response element, may regulate expression of quinone reductase, an enzyme implied in control of ROS and free radicals.…”

Effect of selective estrogen receptor modulators on cell proliferation and estrogen receptor activities in normal human prostate stromal and epithelial cells

“…Contrary to the ERa that is expressed at a higher level in stromal cells and seems to be involved in the pathogenesis of BPH, 2,11 the ERb, through activation by its putative ligand 5a-androstane-3b, 17b-diol, was reported to suppress the growth of the ventral prostate and to decrease the AR content in rodents. 21,22 Accordingly, there have been several studies describing that a loss of ERb expression is seen in high-grade prostate intraepithelial neoplasia and high-grade dysplasia compared with normal prostate epithelium expressing ERb. [23][24][25] Recent experimental studies have demonstrated that ERb behaves as a tumor suppressor gene.…”

The androgen metabolite 5α-androstane-3β,17β-diol (3βAdiol) induces breast cancer growth via estrogen receptor: implications for aromatase inhibitor resistance

“…It has been known for some time that 3βAdiol can bind to both ERα and ERβ with approximately 30-fold and 14-fold lower affinity relative to that of E2, respectively, suggesting slight specificity for ERβ [13]. 3βAdiol has been extensively characterized as an ERβ ligand in in vitro ERβ-promoter driven luciferase assays [18,19], gene expression assays [20,21], and in vivo prostate and prostate cancer models [22,23]. 3βAdiol has been shown to play a well defined role in prostate cancer etiology as an ERβ ligand.…”

“…3βAdiol has been shown to play a well defined role in prostate cancer etiology as an ERβ ligand. Weihua et al demonstrated that 3βAdiol is anti-proliferative in prostate cancer via activation of ERβ [22,23]. The cytochrome P450 CYP7B1 has been shown to be the primary enzyme responsible for the inactivation and elimination of 3βAdiol [24,25].…”