Review
To ERR in the estrogen pathway

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Abstract

Estrogens control a variety of physiological and disease-linked processes, most notably reproduction, bone remodeling and breast cancer, and their effects are transduced through classic nuclear receptors referred to as estrogen receptor-α (ERα) and ERβ. Recent results obtained using the estrogen-related receptors (ERRα, -β and -γ), a subfamily of orphan nuclear receptors closely related to the ERs, have shown that the ERRs share target genes, coregulatory proteins, ligands and sites of action with the ERs. In addition, the ERRs can actively influence the estrogenic response, suggesting that pharmacological modulation of ERR activity will be clinically useful to prevent and/or treat a variety of conditions related to women's health.

Section snippets

The ERs and ERRs are close relatives

The ERR subfamily is now known to comprise three members [ERRα (NR3B1), ERRβ (NR3B2) and ERRγ (NR3B3)], which belong to group III of the nuclear receptor superfamily 3., 4., 5., 6., 7.. Group III also includes ERα and ERβ, in addition to the glucocorticoid (GR; NR3C1), mineralocorticoid (MR; NR3C2), progesterone (PR; NR3C3) and androgen (AR; NR3C4) receptors, which strongly suggests that the ERRs are bona fide steroid receptors (Fig. 1a). The human genome also encodes an ERRα-related pseudogene

Functional kinship and transcriptional crosstalk

Competition for binding sites and coactivators is a key component of transcriptional crosstalk between members of the nuclear receptor superfamily. Group III steroid receptors bind DNA as dimers to hormone response elements comprising two inverted repeats spaced by three nucleotides. The GR, MR, PR and AR recognize response elements containing the consensus half-sites AGAACA, whereas the ERs and ERRs bind to estrogen-response elements (EREs) containing the recognition motif AGGTCA 13., 18., 19.

Shared ligands

Although the ERRs were the first orphan nuclear receptors to be identified, the identity of natural and synthetic ERR ligands remained unknown until recently. In spite of their close structural kinship with the ERs, estradiol and other natural estrogens are not ERR ligands 3., 20.. However, the crystal structure of the liganded ERα 36., 37. indicated that many amino acid residues shown to be crucial for recognition of estradiol are conserved among members of the ER and ERR families [38],

Bone remodeling and breast cancer

Normal bones and breast cancer cells are considered classic estrogen target tissues. Decrease of serum estrogen levels following menopause is associated with the development of osteoporosis, whereas estrogen has long been recognized to play a predominant role in influencing the growth of malignant human breast epithelium. Given the close structural and functional kinship between the ERs and the ERRs, two groups have recently investigated whether the ERRs could participate actively in these

Prospects for enhanced SERMs

It is now clear that the orphan nuclear receptor ERRs and the classic ERs can be considered structurally and functionally part of the same subfamily of nuclear receptors. In particular, the data indicate that SERMs should now include ligands for ERRs. Indeed, the key discovery that DES and OHT, probably the best-characterized and most clinically used synthetic estrogen and SERM, are ERR ligands predicts novel and unexpected uses for current SERMs. Most importantly, these findings will probably

Concluding remarks

The discovery of the first ligands for a subfamily of orphan nuclear receptors often constitutes a decisive turning point in the understanding of the physiological and pharmacological function of these receptors 2., 62., 63., 64.. It appears that a similar fate awaits the ERRs, with the additional benefit that the ERRs have wandered into the path of action of a classic steroid hormone, the roles of which in physiology and diverse pathologies are well characterized.

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