No abstract

No abstract

Many of the effects of estrogens on the uterus are mediated by ERalpha, the predominant ER in the mature organ. Because of the poor reproductive capacity of ERbeta knockout (BERKO) female mice (small litter size, multiple-resorbed fetuses), the role of uterine ERbeta was explored. In the immature uterus, ERalpha and ERbeta are expressed at comparable levels in the epithelium and stroma, and 17beta-estradiol (E(2)) treatment decreases ERbeta in the stroma. The immature uterus of untreated BERKO mice exhibits elevated levels of progesterone receptor (PR) and the proliferation-associated protein, Ki-67. It also exhibits exaggerated responsiveness to E(2), as indicated by enlargement of the lumen, increase in volume and protein content of uterine secretion, induction of the luminal epithelial secretory protein, complement C3, and its regulatory cytokine IL-1beta, and induction of vascular endothelial growth factor and insulin-like growth factor 1 but not its receptor. As expected, E(2) increased PR in the stroma and decreased it in the luminal epithelium of wild-type mice. In the BERKO uterus, E(2) induced PR in the stroma but did not down-regulate it in the epithelium. Increased cell proliferation and exaggerated response to E(2) in BERKO suggest that ERbeta plays a role in modulation of the effects of ERalpha and in addition (or as a consequence of this) has an antiproliferative function in the immature uterus.

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 ...