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Editorial: A New Actor in the Estrogen Receptor Drama—Enter ER-ß

Professor of Physiology, Cell and Structural Biology University of Illinois and College of Medicine Urbana, Illinois 61801-3704

Address all correspondence to: Dr. Benita S. Katzenellenbogen, Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, Illinois 61801-3704. E-mail: katzenel{at}uiuc.edu

	Introduction

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Since the cloning of the estrogen receptor (ER) about 10 years ago (1, 2), there has been the general acceptance that only one ER existed. This contrasted with other members of the nuclear receptor superfamily where multiple forms have been reported (e.g. TR /ß and RAR , ß,) (3, 4). Two recent reports (5, 6) have excited the ER field by identifying a complementary DNA (cDNA) clone encoding a separate subtype, termed ERß. Interestingly, the human and rat ERß clones were identified in cDNA libraries from human testis and rat prostate, tissues not generally considered to be major estrogen target tissues. The new findings bring up many questions. Initially, the most intriguing is how had this second ER eluded investigators for so many years? This is not known, but perhaps only a limited number of major estrogen target cell cDNA libraries were screened.

Do estrogen receptor subtypes ( and ß) mediate distinct biological effects? What are the tissue distributions, ligand selectivities, and biological functions of ER and ERß? Are their functions distinct, overlapping, synergistic, or antagonistic? Are they present in similar or different cells? What biological functions do they play during development and in mature animals of both sexes? The report in this issue of Endocrinology by Kuiper et al. (7) begins to address some of these important issues. ERß has a similar high affinity for estradiol as does the receptor. The authors find that some synthetic and naturally occurring ligands have different relative affinities for ERß vs. , although most ligands bind with similar relative affinity to both subtypes. This suggests that alterations in ligand structure could produce agents that show preferential selectivity for ERß vs. receptors and vice versa. However, the and ß estrogen receptors show high conservation of amino acid sequence in regions of the hormone binding domain known to be important in contacting ligand (8, 9, 10).

Using RT-PCR on RNA from a variety of tissues in the rat (7), the authors compare relative levels of ERß and ER RNA. Some tissues (such as kidney) contain exclusively ER, while other tissues show a great predominance of ER (i.e. uterus, pituitary, epididymis). Other tissues show equal or greater levels of ERß RNA (i.e. ovary, prostate). In brain, ERß appears to be a conspicuous fraction of ER RNA. Thus, ERß may play a significant role in estrogen action in brain, ovary, prostate, and possibly in other tissues. In situ hybridization with cDNA probes to ERß indicate a cell-specific localization in ovary and prostate (5), again implying distinct physiological roles for ERß in these cells. Information on ERß vs. ER concentrations in mammary gland and bone, two important ER targets, not reported on yet, will be eagerly awaited. None of the studies thus far have quantified and compared levels of ER and ERß protein in tissues and cells, which is an important aspect needed to confirm that RNA levels of these two receptors closely parallel their protein expression levels. Development of specific antibodies to ERß, which are now being made, will be of paramount importance for the precise analysis of its cellular protein expression and mechanism of action. ER has a rapid turnover rate in cells (3–4 h; 11–13). Will the same be true for ERß?

In considering the possible biological roles for ERß in estrogen action, it is important to keep in mind that ER and ß have DNA binding domains that are virtually identical–differing by only one amino acid–which suggests that ER and ß receptors interact with similar DNA response elements. However, their A/B domains and activation function-1 (AF-1) regions are quite different, suggesting that their transcriptional activation of different estrogen-responsive genes may show distinctly different patterns because it is now appreciated that gene activation is influenced by promoter- and cell-specific factors (14, 15, 16, 17) and by synergistic interaction between N- and C-terminal receptor activation domains (18). Indeed, compared with ER, ERß is a weaker transactivator of the two gene constructs reported on thus far (1, 2). What would be the activity of an ER/ß heterodimer complex? Is it possible that an ERß specific response element exists or one selectively responsive to an ER/ß heterodimer?

Knock-out mice, in which ERß alone and both ER and ß genes have been inactivated, should be extremely informative in elucidating more fully the endocrine and physiological actions of ERß. Will a double (ER and ß) knockout in mice be lethal? Will they develop properly in utero? Contrary to expectations, the knockout of only ER in mice was not lethal. These ER knockout mice developed to maturity but were infertile and did not respond to estradiol (19, 20, 21). Because estrogen receptors have been shown to be present in the blastocyst (22), are prenatal and postnatal development due to ERß?

Estrogens are known to have important effects in the reproductive system and also in many tissues outside the reproductive system, including bone, liver, and the cardiovascular system (9 and references therein). What roles does ERß vs. play in these tissues in both female and male animals? Because ERß appears to be a conspicuous ER subtype in prostate and testis, will ERß be an important player in the male reproductive system and perhaps in prostate cancer? Does ERß have roles in some of the reported nongenomic actions of estrogens?

Finally, has the full cast of estrogen receptor actors been identified and have they entered the drama? Is there an estrogen receptor or yet to be discovered? There are clearly many exciting new aspects to be explored, which the paper by Kuiper et al. (7) start to answer. The identification of ERß has set off a chain reaction of new experiments that will no doubt help to elucidate the important actors that mediate the diverse and extremely important pleiotropic actions of estrogens in its numerous target tissues. We appear to be just at the start of renewed explorations and most likely the start of the second act of the estrogen drama.

Received January 2, 1997.

	References

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