Abstract
Although the prostate is androgen-dependent, it is also influenced by estrogens, which act via the estrogen receptors ERα and ERβ. In the prostate, ERβ is highly expressed in the epithelium and appears to participate in the regulation of cell proliferation, apoptosis and differentiation. Evidence shows that ERβ is decreased in malignant prostate, suggesting that it plays an important role in protecting this tissue. Despite the relationship between reductions in ERβ and abnormal growth of the gland, little is known about the age-dependent variation of this receptor. Therefore, we aimed to investigate ERβ expression in the prostatic lobes of aging Wistar rats (3 to 24 months). Histopathological alterations, including hyperplasia, intraluminal concretions, nuclear atypia and prostate intraepithelial neoplasias (PIN), were observed in the prostates of aging rats. Epithelial proliferation led to cribriform architecture in some acini, especially in the ventral prostate (VP). In the VP, areas of epithelial atrophy were also observed. Furthermore, in the lateral prostate, there was frequent prostatitis. Immunohistochemistry revealed that the expression of ERβ is reduced in specific areas related to PIN, atrophic abnormalities and cellular atypia in the prostate epithelium of senile rats. Corroborating the involvement of the receptor with proliferative activity, the punctual reduction in ERβ paralleled the increase in cell proliferation especially in areas of PIN and nuclear atypies. The decrease in ERβ reactivity occurred in a hormonal milieu characterized by a constant concentration of estradiol and decreased plasmatic and tissue DHT. This paper is a pioneering study that reveals focal ERβ reduction in the prostate of aging rats and indicates a potential disorder in the ERβ pathway. These data corroborate previous data from humans and dogs that silencing of this receptor may be associated with premalignant or malignant conditions in the prostate.
Highlights
The prostate is a classic androgen-dependent organ, evidence indicates that the gland is influenced by estrogens [1, 2], which can act via the estrogen receptors ERα (ERS1) and PLOS ONE | DOI:10.1371/journal.pone.0131901 July 6, 2015Estrogen Receptor ERβ (ESR2) Expression in Rat Aging ProstateERβ (ERS2) [3]
The initial changes included slight to moderate unfolding of the acinar epithelium, which is suggestive of hyperplasia
From 18 to 24 months of age, the prostatic concretions and the areas of hyperplasia and cellular atypia were more frequently observed and pronounced than those observed at 12 months of age (Fig 1B, 1I, 1M and 1Q), except for the anterior prostate in which the concretion contents did not vary with age
Summary
Estrogen Receptor ERβ (ESR2) Expression in Rat Aging Prostate. The expression of these receptors varies in intensity and distribution in rat and human prostate. In both species, ERα is expressed in few cells of the stroma, whereas ERβ is highly expressed in the epithelium and in some stromal cells [4–7]. Evidence suggests that ERβ expression is highly decreased in malignant prostate tissue, reaching nearly undetectable levels with tumor progression [6, 16–23]. Prostate hyperplasia has been described in mice lacking ERβ (βERKO) [8, 24]. Together, these findings suggest that ERβ plays a role in protecting the prostate against abnormal growth
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