Estrogen dependent signaling in reproductive tissues – A role for estrogen receptors and estrogen related receptors

Molecular and Cellular Endocrinology 348 (2012) 361–372

Contents lists available at SciVerse ScienceDirect

Molecular and Cellular Endocrinology journal homepage: www.elsevier.com/locate/mce

Review

Estrogen dependent signaling in reproductive tissues – A role for estrogen receptors and estrogen related receptors Douglas A. Gibson, Philippa T.K. Saunders ⇑ MRC/UoE Centre for Reproductive Health, The University of Edinburgh, The Queen’s Medical Research Institute, Edinburgh EH16 4TJ, UK

a r t i c l e

i n f o

Article history: Available online 21 September 2011 Keywords: Estrogen receptor Estrogen related receptor Fertility Cancer

a b s t r a c t Estrogens play a fundamental role in the development and normal physiological function of multiple tissue systems and have been implicated in the ontogeny of cancers. The biological effects of estrogens are classically mediated via interaction with cognate nuclear receptors. The relative expression of ER subtypes/variants varies between cells within different tissues and this alters the response to natural and synthetic ligands. This review focuses on the role of estrogen and estrogen related receptors in reproductive tissues. Ó 2011 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5. 6.

7.

8.

Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structure of estrogen and estrogen-related receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Estrogen receptor isoforms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular signaling pathways/functional interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Estrogen receptor related proteins – functional activation and potential cross-talk with estrogen receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . Expression in the normal reproductive tissues and in reproductive cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Ovary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Uterus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Cervix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Testis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5. Efferent ductules, epididymis, vas deferens and seminal vesicles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6. Prostate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Evidence from rodent models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Female reproductive system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Male reproductive system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. Evidence for a functional role for ERRs in mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Background Estrogens play a fundamental role in the development and normal physiological function of multiple tissue systems and have been implicated in the ontogeny of cancers. Estrogens are key regulators of fertility in both males and females. The biological effects of estrogens are classically mediated via their interaction with ⇑ Corresponding author. E-mail address: [email protected] (P.T.K. Saunders). 0303-7207/$ - see front matter Ó 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mce.2011.09.026

361 362 363 364 365 365 365 366 366 366 366 368 368 368 368 369 369 369

nuclear receptors that are members of a superfamily of ligandactivated transcription factors (http://www.nursa.org/). A recent review (Levin, 2010) has provided a comprehensive overview of the ways in which extra-nuclear receptors may also contribute to estrogen-dependent cell signaling and therefore this topic will not be discussed further in the current review. The cDNA of the first estrogen receptor (ER) was cloned in 1986 (Green et al., 1986) and was thought to be the only estrogen receptor gene until a second ER was cloned a decade later (Kuiper et al., 1996). These receptors are known as ERa (NR3A1) and ERb (NR3A2)

362

D.A. Gibson, P.T.K. Saunders / Molecular and Cellular Endocrinology 348 (2012) 361–372

Table 1 Natural and synthetic ligands for ERa, ERb and ERRs. Name

Specificity

Activity

Reference(s)

Suppliers

17b Estradiol (E2)

ERa, ERb

Agonist

Gruber et al. (2002) and Kuiper et al. (1997)

Estrone (E1) PPT (propylpyrazole Triol)

ERa, ERb ERa

Agonist Agonist

DPN (diarylpropionitrile)

ERb>>>ERa

Agonist

Gruber et al. (2002) and Kuiper et al., 1997 Harris et al. (2002), Kraichely et al. (2000) and Stauffer et al. (2000) Meyers et al., 2001

Sigma, Tocris, Cayman Chemicals Sigma, Cayman Chemicals Tocris, Cayman Chemicals

WAY 200070 GSK4716 (GW4716) DY131 Tamoxifen

ERb>>>ERa ERRb/ERRc ERRb/ERRc ERa/ERb

Malamas et al. (2004) Zuercher et al., 2005 Yu and Forman (2005) Dutertre and Smith (2000) and Kuiper et al. (1997)

Raloxifene (LY 139481, keoxifene) MPP dihydrochloride ICI 182,780 (FaslodexTM)

ERa/ERb ERa ERa/ERb

Agonist Agonist Agonist SERM (mixed agonist/ antagonist) SERM (mixed agonist/ antagonist) Antagonist Pure antagonist

XCT790

ERRa

Inverse agonist

Busch et al. (2004) and Lanvin et al. (2007)

Bryant, (2001), Dutertre and Smith (2000) Sun et al. (2002) Wakeling et al. (1991)

and are the products of two genes (ESR1 and ESR2, respectively) located in humans on chromosome 6q25.1 (ESR1) and 14q23.2 (ESR2). ERa and ERb are members of the nuclear receptor subfamily 3 (NR3A); other members of the NR3 subfamily include the orphan estrogen related receptors (NR3B1–3; ERRa, ERRb, ERRc (Tremblay and Giguere, 2007) and the receptors for glucocorticoids (NR3C1, GR), mineralocorticoids (NR3C2, MR), progesterone (NR3C3, PR) and androgens (NR3C4, AR). Members of the NR3C subfamily are discussed in other reviews in this special issue. Evolutionary studies suggest that the ancestral steroid receptor was a functional estrogen receptor the sequence of which was conserved among descendant ERs (Thornton, 2001).

2. Structure of estrogen and estrogen-related receptors ERs and ERRs, like other members of the NR3A family, contain a conserved arrangement of structural and functional domains (A–F) including a conserved DNA-binding domain (DBD, domain C) consisting of two zinc fingers and a C-terminal domain (domain E/F) that contains amino acids involved in ligand binding, receptor dimerisation and nuclear localization (reviewed in Tremblay and Giguere, 2007; Nilsson et al., 2001) (Fig. 1). The ligand binding domains of ERa and ERb have both been crystallized and their three-dimensional structure determined (Pike et al., 1999; Tanenbaum et al., 1998); both consist of 12 helices with amino acids lining the surface of the ligand binding pocket found in helices 3 to 12. Notably key amino acids within this region, designated activation function 2 (AF-2), participate in co-factor recruitment. Molecular modeling has revealed differences in the position of helix 12 as a consequence of binding agonists or antagonists that provide a basis for understanding the relative impacts of these agents on receptor activity (reviewed in Nilsson et al., 2001). Differences in the functional size of the ligand-binding pocket in ERa and ERb facilitate different binding affinity dependent on the structure of the ligand. The varied tissue distribution of ERs and different ligand responses with ER subtypes can have diverse biological affects at the tissue level. Differences in binding affinity and tissue-specific responses to ERa and ERb have driven the development of receptor-selective ligands (Sun et al., 1999; Paruthiyil et al., 2009) some of which are now commercially available (Table 1). Endogenous ligands such as estradiol (E2) and estrone (E1) exhibit agonist activity with both ERs (Gruber et al., 2002). Synthetic receptor-selective ligands including PPT (ERaspecific), DPN (ERb-selective), and the Wyeth compound ERb041,

Tocris, Sigma, Chemicals Tocris, Sigma Tocris, Sigma Tocris, Sigma Sigma, Tocris, Chemicals Sigma, Tocris, Chemicals Tocris, Sigma Sigma, Tocris, Chemicals Tocris, Sigma

Cayman

Cayman Cayman

Cayman

have been used to investigate ER-subtype activity both in vitro and in vivo (Harris et al., 2002; Kraichely et al., 2000; Meyers et al., 2001; Stauffer et al., 2000). These studies have revealed that ERb agonists have potential as therapies in inflammatory bowel disease and rheumatoid arthritis (Harris, 2007), the ERa agonist PPT appears to be neuroprotective (Morissette et al., 2008) and both isotypes of ER may influence the development of cardiovascular disease (Deschamps et al., 2010). Compounds that act as antagonists of both ERa and ERb e.g. ICI 182,780, or ERa alone e.g. MPP dihydrochloride, are available. Selective estrogen receptor modulators (SERMS) have agonist or antagonist properties depending on the cellular/tissue context (Bryant, 2001; Dutertre and Smith, 2000; Sun et al., 2002; Wakeling et al., 1991) (see Table 1). The sequences within the N-terminal (A/B) domains of NR3A family members are poorly conserved with only 20% sequence homology between human ERa and ERb. This domain is involved in protein–protein interactions and in transcriptional activation of target gene expression; it contains the activation function (AF)-1 region as well as several phosphorylation and sumoylation sites (Nilsson et al., 2001; Ascenzi et al., 2006) that are down stream targets for growth factor signaling pathways. Differences in the AF-1 domain may partially explain the distinctive responses of ERa and ERb to some ligands. For example, the anti-estrogens tamoxifen, raloxifene and ICI 164, 384 are partial E2 agonists with ERa and pure E2 antagonists of ERb (Barkhem et al., 1998; McInerney et al., 1998; McDonnell et al., 1995). The orphan receptor proteins ERRa, ERRb and ERRc share significant sequence homology with each other and also with ERa and ERb. Although their putative ligand binding domains exhibit significant amino acid sequence identity with the ER LBDs the ERRs are unable to bind endogenous E2 because they lack the Cys residues involved in ligand recognition in ERa and ERb. However the LBD in ERRs does contain an AF-2 domain that is the site for interaction with co-activators such as PPARc coactivator 1 (PGC1a or b) or corepressors such as RIP140 (Giguere, 2008). The ERR ligand binding pocket is smaller than that in other steroid receptors and it has been postulated that modulation of ERR transcriptional activity is via natural antagonists (Giguere, 2002). Although natural ERR receptor modulators have not yet been identified synthetic compounds that can modulate the function of ERRs are available. For example, diethylstilbesterol (DES) can act as an inverse agonist on all three ERR isoforms (Giguere, 2002) and an inverse agonist called XCT 790 is available for ERRa (Busch et al., 2004). Synthetic agonists of ERRb/ERRc such as GSK 4716 and DY 131 have also been identified (see summary in Table 1).

D.A. Gibson, P.T.K. Saunders / Molecular and Cellular Endocrinology 348 (2012) 361–372

363

Fig. 1. Estrogen receptor isoforms. The 8 exons of the ESR1 (red) and ESR2 (purple) genes that encode the wild type ERa and ERb proteins, respectively are illustrated as numbered boxes. Protein domains are denoted as A to F with numbering denoting amino acid sequence number based on full-length protein. In both ERa and ERb, exon 1 largely encodes the A/B domain that contains the N-terminal transactivation domain (AF-1) a target for phosphorylation. Exons 2 and 3 contribute amino acids to domain C, the DNA binding domain, while exon 4 encodes parts of domains C and E and all of domain D (hinge region). Domain E is also encoded by exons 5, 6 and 7 while exon 8 encodes the remainder of domain E and domain F. Domain E/F contains the LBD and the AF-2 domain. Full length ERa is 595 amino acids in length. ERa-46 results from an alternative start codon and lacks exon 1 resulting in a truncated form of the receptor that is missing the first 173 amino acids of the full-length sequence and lacks the AF-1 domain. ERa-36 is generated form a promoter located in the first intron and lacks exon 1 but also lacks the last 138 amino acids encoded by exons 7 and 8 which are replaced by 27 amino acids at the C-terminus. ERa-36 lacks both AF-1 and AF-2. Full length ERb protein is 530 amino acids in length and has a shorter N terminal domain than ERa. Several common splice variant Isoforms of ERb diverge at common point in the peptide sequence at amino acid 469. In ERb2 this is a result of alternative splicing of exon 8 and results in unique C-terminal amino acid sequences that lack the AF-2 domain. ERb4 and ERb5 are a result of an in frame stop codon in exon 8.

3. Estrogen receptor isoforms Ponglikitmongkol et al. (1988) reported that the human ERa gene is more than 140 kb in length and is split into eight exons. The human ERb gene also contains 8 exons and there is considerable conservation between the arrangement of the coding exon/intron boundaries between human and mouse (Enmark et al., 1997). Human ESR1 and ESR2 are both subject to alternative splicing and although they have similar exon and functional domain organization the splice variant isoforms identified appear to be distinct; as demonstrated by studies that have focused on expression of mRNA variants in cancer cell lines (Poola et al., 2002, 2000). Transcription of the ESR1 gene is initiated from multiple promoters resulting in mRNA isoforms with distinct 50 -untranslated regions (UTR); details of 7 of these are reviewed in Kos et al. (2002). The use of alternative promoters has been implicated in tissue specific patterns of expression and transcriptional regulation (Kos et al., 2002). Truncated isoforms have also been identified (Fig. 1). For example a 46-kDa ERa generated from an internal ATG start codon lacks exon 1 and consequently the N-terminal AF-1 domain (Flouriot et al., 2000). ERa46 can heterodimerize with full length ERa and inhibit AF-1-dependent transcriptional activity (Flouriot et al., 2000). ERa36 is generated from a promoter located in the

first intron and lacks both AF-1 and AF-2 domains (Wang et al., 2005). A number of mRNA isoforms with exon-skipping have also been identified in cell lines (Poola et al., 2000) and a recent paper reported differential expression of ERaD5/6/7, ERaD3/4/5 in preand post-menopausal endometrium (Springwald et al., 2010). The ESR2 gene appears to be particularly prone to alternative splicing with multiple variants formed from use of alternative promoters, inclusion or exclusion of different exons which have been identified in multiple tissues and cell lines. Poola et al. (2002) identified 10 variant mRNA isoforms of the human ESR2 gene with deletions in various combinations of exons several of which were present in extracts prepared from human cell lines and tissues including the ovary. The human ERb (hERb) protein can be expressed as both long (59.2 kDa) and short (53.3 and 54.2 kDa) isoforms (Scobie et al., 2002); these proteins appear to be functionally equivalent in transfection studies (Hall and McDonnell, 1999). In 1998 Ogawa et al. (1998) identified a novel human ERb isoform that they called ERbcx, which was shorter than the wild type protein and had a unique stretch of 26 amino acids at its C-terminus. They demonstrated that these amino acids and an alternative 30 UTR were encoded by a novel exon that was alternatively spliced in place of exon 8. In the same year Moore et al. (1998) identified three full length, and two shortened isoforms of the human ESR2

Cytoplasm of basal and luminal epithelium Weaker Epithelium

+

Cytoplasm of basal epithelium

Some nuclear staining Some nuclear staining Weaker + Prostate Stroma

Low in pachytene spermatocytes + 

Low

Germ cell

+

 

 

Leydig

+ all phases Stroma

Testis Sertoli

Uterus Myometrium Endometrium

Theca Surface epithelium

ND: not described. ⁄ ERa 36/46 only in cancers. High ERRa in ovarian cancers. Staining is nuclear unless stated. Prostatic staining described as ‘weaker’ is relative to staining in other cell types within same tissue.

Prins and Korach (2008), Leung et al. (2010) and Weihua et al. (2002) Prins and Korach (2008), Leung et al. (2010) and Weihua et al. (2002)

Saunders et al. (2002), Makinen et al. (2001) and Sierens et al. (2005) Saunders et al. (2002), Makinen et al. (2001) and Sierens et al. (2005) Saunders et al. (2002), Makinen et al. (2001) and Sierens et al. (2005)

Sakaguchi et al., 2003 Bombail et al. (2010a,b), Critchley et al. (2002) and Bombail et al. (2008) Bombail et al.(2010a,b), Critchley et al. (2002) and Bombail et al. (2008) Pos all phases Pos all phases + + all phases + all phases + + proliferative phase declines during secretory phase + proliferative phase declines during secretory phase

Antral

Epithelium

+

+ + +

+

+ + +



+ + +

Pre-antral

Lower in midsecretory phase

ERb5 ERb2 ERb1 ERa Tissue

Ovary Granulosa

Expression of estrogen receptor and estrogen related receptor protein in normal reproductive tissues determined by immunohistochemistry.

Table 2

ERRa

Pos all phases Pos all phases

Low

ERRb

Scobie et al. (2002), Saunders et al. (2000) and Saunders and Critchley (2002) Saunders et al., 2000 Saunders et al. (2000) and Saunders (2005) Saunders et al. (2000), Saunders (2005)

D.A. Gibson, P.T.K. Saunders / Molecular and Cellular Endocrinology 348 (2012) 361–372

Refs

364

gene that they designated hERb 1–5 (Fig. 1). Notably hERb1 corresponded to the previously described wild type ERb (Ogawa et al., 1998) and ERb2 was identical to ERbcx. All five isoforms had identical sequences until a common position within the predicted helix 10 of the ligand-binding domain consistent with differential exon usage (Moore et al., 1998). All five have been identified in a human testis cDNA library; ERb3 appears to be testis specific but the others have been identified in multiple human tissues as well as a variety of human cell lines (Scobie et al., 2002). The three dimensional structure of the ligand binding domains of hERb2–5 have been solved and all appear to lack an intact binding pocket or a fully functional AF2 domain (Leung et al., 2006; Fig. 1). For example, ERb2 has a shortened C-terminus which results in disoriented helix 12 (which may hinder access to the binding pocket) and shrinkage of the co-activator binding cleft. In ERb4 and ERb5 an in frame stop codon in exon 8 results in a truncated helix 11 and absence of helix 12. Notably the existence of different peptide sequences at the C-terminus of ERb1, 2, 4 and 5 has enabled isoform specific monoclonal and polyclonal antibodies (Scobie et al., 2002; Ogawa et al., 1998; Saunders et al., 2002; Wong et al., 2005) to be developed allowing expression of full length and variant isoforms to be compared (see section below). Alternative splicing of both ESR1 and ESR2 genes appears to be species specific limiting the utility of rodent models in the study of the impact of variant isoforms on tissue responsiveness to estrogens. For example, the ERb2 variants described in rat and mouse both contain in frame insertions of unique peptide sequences within the ligand binding domain resulting in reduced but still detectable ligand bind affinity (Lu et al., 2000; Petersen et al., 1998). Alternative splicing at the C-terminus of the ESR2 gene appears to be conserved in primates with an ERb2 isoform identified in both Stump-tailed macaque and Common marmoset (Sierens et al., 2004). ERRa has no known splice variants. The full-length human ESRRB gene contains 12 exons and three ERRb mRNA splice variants have been identified in human tissues (Zhou et al., 2006). Bombail et al. (2010a) reported expression of both ERRbS [short] and ERRbL [long] mRNAs in human endometrium. ERRc has two splice variants; ERRc2 which is missing 23 N-terminal amino acid residues and has widespread tissue distribution (Chen et al., 1999) and ERRc3 which is missing 39 amino acid residues which correspond to the second Zn finger motif in the DNA binding domain is expressed in adipocytes and prostate (Kojo et al., 2006).

4. Molecular signaling pathways/functional interactions The effects of estrogens can be mediated through several different pathways (reviewed in Nilsson et al., 2001; Hall et al., 2001; Matthews and Gustafsson, 2003). Classically, ligand-activated ERs form homo- or hetero-dimers that interact with response elements (called EREs, estrogen response elements) within the promoter regions of genes (reviewed in Nilsson et al., 2001). Gene transfer and band shift assays were originally used to identify an ERE consensus binding site within the promoter region of the vitellogenin gene of Xenopus laevis (Klein-Hitpass et al., 1989) this sequence was shown to consist of a palindromic repeat 50 -GATCTAGGTCACAGTGACCTA-30 . It has been reported that the binding affinity of ERa–ERa homodimers and ERa–ERb heterodimers for consensus EREs is higher than ERb–ERb homodimers (Cowley et al., 1997). Subsequent studies have established that estrogen receptors can also bind imperfect EREs and half sites, and can bind indirectly via other factors (reviewed in Nilsson et al., 2001; Welboren et al., 2007).

D.A. Gibson, P.T.K. Saunders / Molecular and Cellular Endocrinology 348 (2012) 361–372

Key to our understanding of the range of ER binding sites has been the application of the method of chromatin immunoprecipitation (ChIP) in combination with genome-wide tiling arrays (ChIP-chip) or other methods (ChIP-PET, ChIP-seq). Most of these studies have used antibodies directed against ERa and have been performed using cancer cell lines such as MCF-7. They have revealed a potentially complicated regulation network with only a small portion of ERa binding sites being located in the promoter regions of known genes and many unforeseen binding sites a long distance from the putative transcription start site (Carroll et al., 2006). In a recent paper Gu et al. used informatics to reanalyze several of these datasets and they reported significant differences in the transcriptional networks in MCF-7 cells that were tamoxifen resistant (Gu et al., 2010). These studies have also revealed a role for other transcription factors in ER-dependent recruitment to EREs (reviewed in Welboren et al., 2007). Fewer studies have been conducted examining the ERb-dependent transcriptome. In ERa-positive MCF-7 cells engineered with an inducible ERb gene construct Li et al. (2008) found a high degree of overlap between the regions bound by ERa and ERb, regions that were bound by ERa only in the presence of ERa, as well as regions that are bound by either receptor. Chang et al. (2008) used adenoviral delivery to engineer the relative expression of ERs. They reported that the phytoestrogen genistein preferentially activated ERb and proposed that differential occupancy of ERa and ERb by genistein and E2 could influence recruitment patterns of co-regulatory proteins with knock-on consequences for patterns of gene expression. Genomic studies have also revealed that only a third of the estrogen-responsive genes so far identified contain sequences in their promoters that resemble EREs (O’Lone et al., 2004). ER complexes can also bind through a variety of protein–protein interactions with transcription factors tethered to DNA such as Jun/Fos (at AP-1 response elements) or SP-1 (at GC-rich SP-1 motifs) or by interaction with the NFj b pathway (De Bosscher et al., 2006). ERs acting at different response elements may have agonist and antagonist profiles that differ from classical mechanisms of ER action; for example when tethered via AP-1 sites ERa exhibits E2dependent activation of transcription at AP-1 sites, whereas E2 bound to ERb has no effect (Paech et al., 1997). Both ERa and ERb can interact with Sp transcription factors and while ERa–Sp1 complexes can be activated by estrogens little transcriptional activation is observed for Sp1-ERb complexes. This may be due to AF-1 differences between the receptors (Saville et al., 2000). The antiestrogen ICI 182, 780 is a potent agonist to ERa and ERb when they are tethered to AP-1, SP-1 and (O’Lone et al., 2004) STAT-5 transcription factors in the nucleus (Bjornstrom and Sjoberg, 2005). The affinities of different cofactors for ERs can also be subtype specific, for example, thyroid receptor-associated protein 220 (TRAP220) interacts with both ER subtypes but has selective affinity for ERb (Kang et al., 2002). In the presence of E2 the co-activator SRC-1 can be recruited to either ER but in the presence of genistein is more strongly recruited to ERb (Routledge et al., 2000). The role of cofactors in nuclear receptor function is reviewed elsewhere in this issue. To date our understanding of the potential impact of expression of ERb splice variants on estrogen responsiveness has been limited to studies using in vitro reporter systems. Co-expression of ERb1 with ERa can result in a concentration dependent reduction in ERa-mediated transcriptional activity (Paech et al., 1997; Liu et al., 2002). Leung et al. (2006) reported that the ability of ERb1 to activate an ERE-luciferase reporter gene in the presence of E2 was enhanced by co-expression of ERb2, b4 or b5. In other studies it was reported that ERb2 shows preferential hetero-dimerisation with ERa rather than ERb, inhibiting ERa DNA binding and having a dominant-negative effect on ligand-dependent ERE reporter gene activity (Ogawa et al., 1998).

365

5. Estrogen receptor related proteins – functional activation and potential cross-talk with estrogen receptors Binding site selection experiments have demonstrated that ERR

a binds to a response element (ERRE) containing a single consensus half-site, TNAAGGTCA, as either a monomer or a dimer (Sladek et al., 1997). It has been reported that ERs and ERRs have the capacity for transcriptional cross-talk with E-dependent genes such as osteopontin (reviewed in Vanacker et al., 1999). More recently studies using genomic analyses of binding sites have reported that ERRa and ERa display strict binding site specificity and maintain independent mechanisms of transcriptional activation (Deblois et al., 2009). One mechanism of action for ERRs is by interaction with other transcription factors including ERs. For example ERRb is reported to repress NF-E2 Related Factor 2 (Nrf2) activity via the antioxidant response element (ARE) through physical interaction in a complex with Nrf2 and consistent with this ERRb appears to be able to alter the subcellular localization of Nrf2 (Zhou et al., 2007). Isoforms of ERRb can also differentially impact on ERadependent gene expression and this may in part relate to direct interaction between the proteins (Bombail et al., 2010a). Surprisingly androgen responsive genes can be down-regulated by inhibition of ERRa suggesting further capacity for cross-talk (Teyssier et al., 2008). Although the diverse functions of ERRs are yet to be fully explored in the reproductive system it is notable that a recent review claimed they are master regulators of mitochondrial biogenesis and function (Eichner and Giguere, 2011). 6. Expression in the normal reproductive tissues and in reproductive cancers Estrogen receptors are widely expressed in reproductive tissues details are given in the following sections and summarised in Table 2. 6.1. Ovary The ovary is the most important site of biosynthesis of estrogens in non-pregnant women of reproductive age. Expression of the aromatase enzyme complex, responsible for the conversion of theca-derived androgens, is up-regulated in mural granulosa cells of mature, antral follicles and also expressed in cells within the corpus luteum (Turner et al., 2002). Immunohistochemical studies in rodents (Saunders et al., 1997), primates and human (Saunders et al., 2000) have documented expression of ERb in all somatic cell types with intense staining of granulosa cells in immature and mature (antral) follicles as well as in the theca, corpus luteum and ovarian surface epithelium. In human ovaries immunoexpression of ERa appeared restricted to the surface epithelium, theca cells and granulosa cells of mature follicles (Saunders et al., 2000; Pelletier and El-Alfy, 2000). Messenger RNAs encoding hERb2 and hERb4 have been detected in isolated human granulosa cells and their respective proteins immunolocalized to the same cell type in immature follicles (Scobie et al., 2002). The vast majority (90%) of ovarian cancers arise from the surface epithelium of the ovary (epithelial cell type) with the remainder arising from the granulosa cell (5%) or the germ cell (1–2%) (http:// www.cancerhelp.org.uk/type/ovarian-cancer/about/types-of-ovarian-cancer). Local biosynthesis of estrogen may occur in ovarian cancers as aromatase is reported to be expressed in up to 80% of ovarian cancers. According to Li et al. (2008) in patients with recurrent ovarian cancer, for whom therapeutic options are limited, treatment with aromatase inhibitors has been shown to elicit clinical response rates of up to 35.7% and stable disease rates of 20–42% making them attractive options for treatment in this group of patients. In

366

D.A. Gibson, P.T.K. Saunders / Molecular and Cellular Endocrinology 348 (2012) 361–372

recent papers Halon et al. (2011) claimed that loss of ERb expression in ovarian tumors may be a feature of malignant transformation and patients with a lower immunoreactivity score of ERa expression had significantly shorter overall survival time. Chu et al. (2000) demonstrated that expression of full length ERb was higher in granulosa cell tumors than in those of epithelial origin and that ERb2 (ERbcx) mRNA was widely expressed. In a subsequent paper they postulated that transcriptional resistance in ER-positive granulosa cell tumors was due to trans-repression by NFj b (Chu et al., 2004). Expression of ERRa mRNA has been detected in normal ovaries and is reportedly increased with clinical stage in ovarian cancers regardless of histopathological type; ERRb and ERRc mRNA expression was low in the same study (Fujimoto et al., 2007).

6.2. Uterus The uterus has an outer muscular layer, the myometrium, which surrounds the endometrium that comprises a basal and functional layer. The functional layer of the endometrium undergoes cyclical growth, differentiation and regeneration under the influence of ovarian steroid hormones in the normal menstrual cycle and in the absence of pregnancy is shed during menses (Critchley and Saunders, 2009). Expression of ERs and ERRs is temporally and spatially regulated. In the myometrium ERa and ERb are both expressed but ERa mRNA expression is higher than ERb (Jakimiuk et al., 2004). In the myometrium of postmenopausal women there is a switch in the relative expression of mRNAs with increased expression of ERb and decreased expression of ERa compared to premenopausal myometrium. These changes are likely to be related to differences in bioavailable estrogens. During pregnancy there is a switch to predominance of ERb over ERa in term myometrium (Sakaguchi et al., 2003). In the normal pre-menopausal endometrium the ratio of ERa to ERb changes according to the stage of the menstrual cycle. In the estrogen dominated proliferative phase, ERa expression is high in the glands and stroma (Critchley et al., 2001) (Fig. 2a) but ERa expression decreases in the secretory phase following the postovulatory rise in progesterone (Critchley et al., 2002). In Fallopian tube, ERa mRNA is not down-regulated by peak progesterone levels and expression remains constant throughout the menstrual cycle (Horne et al., 2009). ERb1 mRNA and protein are expressed throughout the cycle (Fig. 2b); ERb2 is higher in the proliferative phase and is selectively down-regulated in the glandular epithelium during the secretory phase. In the uterus both ERa and ERb proteins are expressed in multiple cell types, including the stroma and epithelial cells. ERb but not ERa can be detected in endothelial cells that line blood vessel walls (Critchley et al., 2001) (Fig. 2c) and in immune cells such as uterine-specific natural killer (uNK) cells (Fig. 2d and e) (Henderson et al., 2003). In decidua of early pregnancy ERa expression is minimal and restricted to nuclei of stromal and epithelial cells but nuclear expression of ERb is found in all compartments (Milne et al., 2005). ERRs are also expressed in the uterus (Table 2). ERRa protein is expressed in the epithelial cells of glands, in stromal cells and endothelial cells at all stages of the cycle (Fig. 2f). A recent study reported increased expression of ERRa associated with decidualisation of endometrial stromal cells in vitro; XCT790, an ERRa inverse agonist, inhibited expression of both ERRa and decidualisation markers such as IGFBP1 (Bombail et al., 2010b). ERRb is expressed in human placenta (Fig. 2g) and has been localized to cell nuclei within the glands, stroma, endothelium and immune cells of the human endometrium throughout the cycle (Fig. 2h). In macrophages, uNK cells and endothelial cells ERRb was co-expressed with ERb. In epithelial cells during the prolifera-

tive phase ERRb was co-expressed with ERa (Bombail et al., 2008). ERRc has not been described in the uterus. Endometrial cancer is the most common gynaecological malignancy. Greatest risk of developing the disorder is associated with factors related to excess exposure to estrogen, unopposed by progesterone, and a pro-inflammatory environment (Wallace et al., 2010). In a recent study Collins et al. (2009) reported that expression of ERa was reduced in poorly differentiated grade I cancers compared to those graded as well or moderately differentiated adenocarcinomas. In the same tissue set mRNAs encoding ERb1, ERb2 and ERb5 did not vary significantly according to grade. The same isoforms were localized to cell nuclei in both the epithelial and stromal compartments with intense immunoexpression of ERb5 regardless of grade (Collins et al., 2009). In a separate study by Fujimoto and Sato (2009) the authors reported that a decrease in expression of both ERa and ERb mRNAs correlated with a more advanced clinical stage, myometrial invasion and de-differentiation. In the same sample set expression of ERRa mRNA increased with clinical stage and myometrial invasion regardless of differentiation (Fujimoto and Sato, 2009). 6.3. Cervix Expression of both ERa and ERb has been described in stromal and epithelial cells, and in glandular epithelium of the cervix (Taylor and Al-Azzawi, 2000). Cervical vascular endothelium and cervical leukocytes express only ERb (Stygar et al., 2001). During pregnancy the human cervix undergoes tissue remodeling in preparation for parturition which is associated with an increase in ERb at term compared to non-pregnant cervix (Wang et al., 2001). Cervical cancer is often ERa positive and ERa is required for carcinogenic activities of estrogen in the cervix (Chung et al., 2010). However carcinoma in situ of the cervix has been shown not to express ER (Chaudhuri et al., 1992). Studies in HPV transgenic mouse models suggest estrogen in combination with HPV oncogenes may promote cervical cancer (Chung et al., 2008). 6.4. Testis Immunoexpression of ERa has not been detected in the adult human testis (Saunders et al., 2002; Makinen et al., 2001). Messenger RNA to multiple ERb isoforms (ERb1–5) have been isolated from cDNA pools prepared from human testis (Moore et al., 1998); ERb2 and ERb4 mRNA are reported to be expressed in germ cell enriched cell fractions (Aschim et al., 2004). Immunoexpression of ERb1 (Fig. 2i), and ERb2 has been documented in distinct cell populations (Saunders et al., 2002). For example, immunostaining for ERb1 was intense in pachytene spermatocytes and round spermatids but lower in Sertoli cells, spermatogonia and preleptotene, leptotene, zygotene and diplotene spermatocytes. Intense immunoexpression of ERb2 has been described in Sertoli cells and spermatogonia but is variable in preleptotene, pachytene, and diplotene spermatocytes. Low and variable expression of both ERb1 and ERb2 was detected in peritubular myoid and Leydig cells (Saunders et al., 2002). In isolated human germ cells the ERa46 protein has been detected in spermatozoa (Carreau et al., 2006). In mice ERRa is expressed in seminiferous tubules and in adults is restricted to cells corresponding to spermatocytes (Vanacker et al., 1998). 6.5. Efferent ductules, epididymis, vas deferens and seminal vesicles In the male urogenital system of rodents and man the highest levels of expression of ERa have been detected in the efferent ductules that connect the testis to the head of the epididymis (Atanassova et al., 2001; Saunders et al., 2001). Expression of ERa in

D.A. Gibson, P.T.K. Saunders / Molecular and Cellular Endocrinology 348 (2012) 361–372

367

Fig. 2. Immunolocalisation of ERs and ERRs in reproductive tissues. (a) ERa, human endometrium from proliferative phase, note intense staining of nuclei in endometrial glandular epithelium (G) (b) ERb, human endometrium from secretory phase with immunopositive cells in glandular (G) and luminal epithelium as well as within the stromal compartment, blood vessel circled (c) High power view of endometrial blood vessel showing ERb positive endothelial cells (arrowhead) (d and e) double fluorescent immunostaining for uterine natural killer cells (CD56+, red, surface maker) in combination with ERa (d, green) or ERb (e, green), note that CD56 positive cells are only immunopositive for ERb (arrows in panel e). (f) ERRa, human endometrium. Note immunopositive staining of nuclei of cells lining the glands (G), stromal fibroblasts (S) and endothelial cells (arrowhead) (g) ERRb, human placenta, first trimester. Immunopositive cell nuclei were detected in the cytotrophoblast cells but not in syncytiotrophoblast. (h) ERRb, human endometrium, late secretory phase. The protein was expressed in nuclei of cells lining the glands (G), within the stroma and also both endothelial and perivascular cells lining blood vessels (rings). (i) ERb, adult human testis. Immunopositive cell nuclei were detected in both interstitial (Leydig cells, LC and blood vessels, BV) as well as within multiple cell types within the seminiferous tubules (ST) including Sertoli cells. Although intense immunopositive staining was detected in germ cells including pachytene spermatocytes and round spermatids (arrowheads) some pre-meiotic germ cells were immunonegative (open arrow). (j) ERa, human prostate. Immunopositive staining was detected in basal cells. (k) ERb, human prostate. Protein was widely expressed in cells lining the glandular epithelium (E) and also in the stroma (S).

368

D.A. Gibson, P.T.K. Saunders / Molecular and Cellular Endocrinology 348 (2012) 361–372

the epididymis is more variable and species specific. In human and primate expression of ERa was rarely detected in epithelial, basal cells or stromal cells but was more frequent in stromal cells of seminal vesicles. In contrast ERb was detected in epithelial and stromal cell nuclei throughout the male reproductive system including the efferent ductules, epididymis, vas deferens and seminal vesicles (Saunders et al., 2001). ERb2 and ERb4 are both expressed in epithelial cells lining the vas deferens (Scobie et al., 2002). 6.6. Prostate Estrogens have a significant effect on the development and homeostasis of the prostate gland and may have an important influence in prostatic diseases (reviewed in Ellem and Risbridger, 2010). ERa is predominantly expressed in the stromal compartment (Fig. 2j). A study by Cheung et al. examined expression of ERs and ERRs in a range of prostate cell lines. ERa was weakly expressed in normal prostate epithelial cells, strongly expressed in the immortalized cell line RWPE-1, moderately expressed in the prostate cancer cell line PC3, but not in LNCaP or DU145 cell lines (Cheung et al., 2005). ERb is the dominant ER isoform in the prostatic epithelium and is thought to inhibit proliferation and promote differentiation (Fig. 2j) Prins and Korach, 2008. Leung et al. reported cytoplasmic staining of ERb2 in basal and luminal epithelial cells and some nuclear staining in stromal cells; ERb5 was strongly localized to basal epithelial cells and weakly stained some stromal cells (Leung et al., 2010). In cultured cells ERb is reported to be low in normal prostate epithelial cells, moderate in the immortalized cell line RWPE-1, and moderate to strong in the prostate cancer cell lines PC3, LNCaP and DU145 (Cheung et al., 2005). A recent study by Miao et al. described high expression of ERRa in WPMY-1, a human normal prostate stromal cell line. In this study increased expression of ERRa in response to prostaglandin (PGE)2 also contributed to local estradiol production by upregulating aromatase expression (Miao et al., 2010). Cheung et al. described strong expression of ERRs in prostate cell lines, for example, ERRb was strongly expressed in normal prostate epithelial cells and RWPE-1 but was only weakly expressed in PC3 and DU145. ERRc was expressed strongly in RWPE-1, LNCaP and PC3 but only weakly in DU145 and normal prostate epithelial cells. (Cheung et al., 2005). It has been claimed that development of prostate cancer is associated with decreased expression of ERb but expression may be regained in metastasis. In prostate cancer ERb2 and ERb5 expression have prognostic value. In patient samples, nuclear expression of ERb2 and cytoplasmic expression of ERb5 are both associated with an increased risk of reduced survival. In the same study the authors reported that over-expression of ERb2 or ERb5 in PC-3 cells resulted in a more invasive cell phenotype (Leung et al., 2010). In another study Fujimura et al. reported higher expression of ERb2 and lower expression of ERb1 in malignant prostatic tissue compared to benign tissue (Fujimura et al., 2001). 7. Evidence from rodent models 7.1. Female reproductive system The estrogen receptor a knockout (ERaKO) mouse has an ovarian phenotype that is characterized by cystic and hemorrhagic follicles as well as anovulation. Couse et al. (1999) showed this phenotype could be reversed by addition of exogenous gonadotropin concluding the ovarian phenotype was due to disruption of the HPA axis. It was noted that ERaKO mice had an inefficient ovula-

tory capacity that may suggest an intra-ovarian role for ERa (Couse et al., 1999). The ovaries of theca-specific estrogen receptor a knockout (ThERaKO) mice show erratic oestrous and infertility from 4 months of age. Such ovaries have fewer corpora lutea and more antral follicles and superovulation stimulated the release of fewer oocytes of poor quality compared to wild types (Lee et al., 2009). The ovaries of the ThERaKO displayed some signs of hemorrhagic cyst formation that was enhanced with gonadotropin treatment (Lee et al., 2009). These findings suggest that loss of ERa in the theca may contribute to the ovarian phenotype in the global ERaKO mouse. Studies on ERbKO mice show that the ovaries have reduced ovarian efficiency characterized by more early atretic follicles and reduced number of corpora lutea compare to wild-type ovaries. Numbers and size of litters is reduced and superovulation of ERbKO resulted in reduced number of oocytes (Krege et al., 1998). Large antral follicles of ERa+/-ERbKO and ERabKO adults are markedly deficient in granulosa cells (Dupont et al., 2000). It has been reported that trans/re-differentiation of granulosa cells occurs in the double knockouts resulting in a ‘Sertoli cell-like’ phenotype (Couse et al., 1999). In the aromatase knockout mouse (ArKO) ovarian function is disrupted due to arrested follicular development at the antral stage rendering the mice infertile (reviewed in Drummond et al., 2002). Further evidence of the specific role of ERs in ovarian function is evidenced from the use of isotype-selective ER agonists. HegeleHartung et al. used highly selective agonists to ERa (16aLE2) and ERb (8b-VE2) to investigate the impact on ovarian function in rats. Treatment with 8b-VE2 stimulated early folliculogenesis, decreased follicular atresia, induction of ovarian gene expression and stimulation of late follicular growth accompanied by an increase in oocytes without having stimulatory effects on uterine growth. Conversely treatment with the ERa agonist 16aLE2 had a little or no ovarian effect but stimulated uterine growth (Hegele-Hartung et al., 2004). The uterus is a major target tissue for estrogen action. Female ERaKO mice exhibit uterine hypoplasia with uterine weights that are half that of wild types with sparse distribution of glands (Dupont et al., 2000; Lubahn et al., 1993). The decidual response is intact but there is implantation failure (Curtis Hewitt et al., 2002). A uterine epithelial cell-specific ERa knock out model has also been reported and the studies on this mouse have demonstrated that proliferation of epithelial cells is mediated by an ERa-dependent proliferative signal from the stroma (Winuthayanon et al., 2010). In ERbKO mice uterine weight is normal however loss of functional ERb results in reduced epithelial cell differentiation and the ERbKO females are hyper-responsive to the proliferative effects of E2 consistent with a role for ERb as a negative regulator of ERa mediated response in this tissue (Dupont et al., 2000). 7.2. Male reproductive system Estrogen has an important, although poorly understood, physiological role in regulating male reproductive organs. Notably, local biosynthesis of estrogen occurs in the testis with expression of aromatase being detected in Leydig cells and some populations of germ cells (Turner et al., 2002); ArKO mice develop a late onset testicular phenotype that can be partially reversed by a diet rich in phytoestrogens (Robertson et al., 2002). ERaKO male mice have a normal testicular phenotype until puberty but thereafter begin to degenerate and become atrophic due to a failure of resorption of fluid by the cells lining the efferent ductules creating ‘back pressure’ within the testis resulting in collapse of the seminiferous epithelium (Eddy et al., 1996; Hess et al., 1997). Male mice with targeted deletions of ERb appear to have a normal testicular phenotype (Krege et al., 1998; Dupont et al., 2000).

D.A. Gibson, P.T.K. Saunders / Molecular and Cellular Endocrinology 348 (2012) 361–372

Estrogens exert both direct and indirect effects on prostatic tissues and changes in the androgen: estrogen ratio in aging men has been cited as a risk for development of prostatic disorders including benign prostatic hyperplasia and cancer (Ellem and Risbridger, 2010). Studies in mice have not revealed a prostatic phenotype in ERaKO males (Jarred et al., 2002) suggesting ERa is not necessary for normal growth and development and although prostatic epithelial hyperplasia has been claimed in some lines of ERbKO mice (Krege et al., 1998) this has been disputed by others (Dupont et al., 2000). Studies using tissue recombinations and treatments with an ERb-specific agonist suggest that stimulation of ERb elicits antiproliferative responses in epithelium suggesting that selective stimulation of ERb could benefit prostate health and inhibit disease development/progression (McPherson et al., 2007). 7.3. Evidence for a functional role for ERRs in mice In adult mice ERRa is expressed in the kidney, heart, brown adipose tissue and tissues that preferentially metabolise fatty acids (Ranhotra, 2010). Evidence that ERRa is involved in energy homeostasis has come from studies in ERRaKO mice demonstrating they have resistance to diet induced obesity, altered fat metabolism and adsorption (Luo et al., 2003). They also fail to maintain body temperature in response to cold and have altered response to cardiac overload (Huss et al., 2007). ERRb is expressed during a narrow developmental window in trophoblast progenitor cells and is thought to play a role in early placentation consistent with impaired placental function in ERRbKO (Fujimoto et al., 2005). ERRc is expressed in the central nervous system and is essential in oxidative metabolism of the heart; mice with targeted disruption of Esrrg suffer from heart abnormalities and die during the first week of life (Alaynick et al., 2007). 8. Future perspectives Estrogen receptors play an essential role in the development and normal physiological function of reproductive and other tissues. The relative expression of both full length and variant isoforms of ERs varies between cells within different tissues and this, together with variations in ligand availability adds to the complexity of responses to natural and synthetic ligands. Cancers of reproductive tissues are often hormone responsive and this has prompted the development of therapies based on SERMS and estrogen receptor subtype specific agonists. The impact of ER variants on cell function remains poorly understood as does the relative importance of non-ERE dependent signaling in defining the ER ‘transcriptome’ and both these topics require further investigation. New insight into the relative contributions of ERs to disease susceptibility may also come from the increasing number of studies examining single nucleotide polymorphisms in their genes (Chen et al., 2007). There is an increasing body of evidence that ERRs may play a role in regulation of cell metabolism (Eichner and Giguere, 2011) but the full impact of this class of nuclear receptor on steroid responsiveness will require further study. References Alaynick, W.A., Kondo, R.P., Xie, W., He, W., Dufour, C.R., Downes, M., Jonker, J.W., Giles, W., Naviaux, R.K., Giguere, V., Evans, R.M., 2007. ERRgamma directs and maintains the transition to oxidative metabolism in the postnatal heart. Cell Metab. 6, 13–24. Ascenzi, P., Bocedi, A., Marino, M., 2006. Structure-function relationship of estrogen receptor alpha and beta: impact on human health. Mol. Aspects Med. 27, 299– 402. Aschim, E.L., Saether, T., Wiger, R., Grotmol, T., Haugen, T.B., 2004. Differential distribution of splice variants of estrogen receptor beta in human testicular cells suggests specific functions in spermatogenesis. J. Steroid Biochem. Mol. Biol. 92, 97–106.

369

Atanassova, N., McKinnell, C., Williams, K., Turner, K.J., Fisher, J.S., Saunders, P.T., Millar, M.R., Sharpe, R.M., 2001. Age-, cell- and region-specific immunoexpression of estrogen receptor alpha (but not estrogen receptor beta) during postnatal development of the epididymis and vas deferens of the rat and disruption of this pattern by neonatal treatment with diethylstilbestrol. Endocrinology 142, 874–886. Barkhem, T., Carlsson, B., Nilsson, Y., Enmark, E., Gustafsson, J., Nilsson, S., 1998. Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. Mol. Pharmacol. 54, 105–112. Bjornstrom, L., Sjoberg, M., 2005. Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol. Endocrinol. 19, 833–842. Bombail, V., MacPherson, S., Critchley, H.O., Saunders, P.T., 2008. Estrogen receptor related beta is expressed in human endometrium throughout the normal menstrual cycle. Hum. Reprod. 23, 2782–2790. Bombail, V., Collins, F., Brown, P., Saunders, P.T., 2010a. Modulation of ER alpha transcriptional activity by the orphan nuclear receptor ERR beta and evidence for differential effects of long- and short-form splice variants. Mol. Cell Endocrinol. 314, 53–61. Bombail, V., Gibson, D.A., Collins, F., MacPherson, S., Critchley, H.O., Saunders, P.T., 2010b. A Role for the orphan nuclear receptor estrogen-related receptor alpha in endometrial stromal cell decidualization and expression of genes implicated in energy metabolism. J. Clin. Endocrinol. Metab. 95, E224–E228. Bryant, H.U., 2001. Mechanism of action and preclinical profile of raloxifene, a selective estrogen receptor modulation. Rev. Endocr. Metab. Disord. 2, 129– 138. Busch, B.B., Stevens Jr., W.C., Martin, R., Ordentlich, P., Zhou, S., Sapp, D.W., Horlick, R.A., Mohan, R., 2004. Identification of a selective inverse agonist for the orphan nuclear receptor estrogen-related receptor alpha. J. Med. Chem. 47, 5593–5596. Carreau, S., Delalande, C., Silandre, D., Bourguiba, S., Lambard, S., 2006. Aromatase and estrogen receptors in male reproduction. Mol. Cell Endocrinol. 246, 65–68. Carroll, J.S., Meyer, C.A., Song, J., Li, W., Geistlinger, T.R., Eeckhoute, J., Brodsky, A.S., Keeton, E.K., Fertuck, K.C., Hall, G.F., Wang, Q., Bekiranov, S., Sementchenko, V., Fox, E.A., Silver, P.A., Gingeras, T.R., Liu, X.S., Brown, M., 2006. Genome-wide analysis of estrogen receptor binding sites. Nat. Genet. 38, 1289–1297. Chang, E.C., Charn, T.H., Park, S.H., Helferich, W.G., Komm, B., Katzenellenbogen, J.A., Katzenellenbogen, B.S., 2008. Estrogen receptors alpha and beta as determinants of gene expression: influence of ligand, dose, and chromatin binding. Mol. Endocrinol. 22, 1032–1043. Chaudhuri, B., Crist, K.A., Mucci, S.J., Thomford, N.R., Chaudhuri, P.K., 1992. Estrogen receptor in carcinoma in situ of the cervix. J. Surg. Oncol. 49, 103–106. Chen, F., Zhang, Q., McDonald, T., Davidoff, M.J., Bailey, W., Bai, C., Liu, Q., Caskey, C.T., 1999. Identification of two hERR2-related novel nuclear receptors utilizing bioinformatics and inverse PCR. Gene 228, 101–109. Chen, Y.C., Kraft, P., Bretsky, P., Ketkar, S., Hunter, D.J., Albanes, D., Altshuler, D., Andriole, G., Berg, C.D., Boeing, H., Burtt, N., Bueno-de-Mesquita, B., Cann, H., Canzian, F., Chanock, S., Dunning, A., Feigelson, H.S., Freedman, M., Gaziano, J.M., Giovannucci, E., Sanchez, M.J., Haiman, C.A., Hallmans, G., Hayes, R.B., Henderson, B.E., Hirschhorn, J., Kaaks, R., Key, T.J., Kolonel, L.N., LeMarchand, L., Ma, J., Overvad, K., Palli, D., Pharaoh, P., Pike, M., Riboli, E., Rodriguez, C., Setiawan, V.W., Stampfer, M., Stram, D.O., Thomas, G., Thun, M.J., Travis, R.C., Virtamo, J., Trichopoulou, A., Wacholder, S., Weinstein, S.J., 2007. Sequence variants of estrogen receptor beta and risk of prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. Cancer Epidemiol. Biomarkers Prev. 16, 1973–1981. Cheung, C.P., Yu, S., Wong, K.B., Chan, L.W., Lai, F.M., Wang, X., Suetsugi, M., Chen, S., Chan, F.L., 2005. Expression and functional study of estrogen receptor-related receptors in human prostatic cells and tissues. J. Clin. Endocrinol. Metab. 90, 1830–1844. Chu, S., Mamers, P., Burger, H.G., Fuller, P.J., 2000. Estrogen receptor isoform gene expression in ovarian stromal and epithelial tumors. J. Clin. Endocrinol. Metab. 85, 1200–1205. Chu, S., Nishi, Y., Yanase, T., Nawata, H., Fuller, P.J., 2004. Transrepression of estrogen receptor beta signaling by nuclear factor-kappab in ovarian granulosa cells. Mol. Endocrinol. 18, 1919–1928. Chung, S.H., Wiedmeyer, K., Shai, A., Korach, K.S., Lambert, P.F., 2008. Requirement for estrogen receptor alpha in a mouse model for human papillomavirusassociated cervical cancer. Cancer Res. 68, 9928–9934. Chung, S.H., Franceschi, S., Lambert, P.F., 2010. Estrogen and ERalpha: culprits in cervical cancer? Trends Endocrinol. Metab. 21, 504–511. Collins, F., MacPherson, S., Brown, P., Bombail, V., Williams, A.R., Anderson, R.A., Jabbour, H.N., Saunders, P.T., 2009. Expression of oestrogen receptors, ERalpha, ERbeta, and ERbeta variants, in endometrial cancers and evidence that prostaglandin F may play a role in regulating expression of ERalpha. BMC Cancer 9, 330. Couse, J.F., Bunch, D.O., Lindzey, J., Schomberg, D.W., Korach, K.S., 1999. Prevention of the polycystic ovarian phenotype and characterization of ovulatory capacity in the estrogen receptor-alpha knockout mouse. Endocrinology 140, 5855– 5865. Couse, J.F., Hewitt, S.C., Bunch, D.O., Sar, M., Walker, V.R., Davis, B.J., Korach, K.S., 1999. Postnatal sex reversal of the ovaries in mice lacking estrogen receptors alpha and beta. Science 286, 2328–2331. Cowley, S.M., Hoare, S., Mosselman, S., Parker, M.G., 1997. Estrogen receptors alpha and beta form heterodimers on DNA. J. Biol. Chem. 272, 19858–19862. Critchley, H.O., Saunders, P.T., 2009. Hormone receptor dynamics in a receptive human endometrium. Reprod. Sci. 16, 191–199.

370

D.A. Gibson, P.T.K. Saunders / Molecular and Cellular Endocrinology 348 (2012) 361–372

Critchley, H.O., Brenner, R.M., Henderson, T.A., Williams, K., Nayak, N.R., Slayden, O.D., Millar, M.R., Saunders, P.T., 2001. Estrogen receptor beta, but not estrogen receptor alpha, is present in the vascular endothelium of the human and nonhuman primate endometrium. J. Clin. Endocrinol. Metab. 86, 1370– 1378. Critchley, H.O., Henderson, T.A., Kelly, R.W., Scobie, G.S., Evans, L.R., Groome, N.P., Saunders, P.T., 2002. Wild-type estrogen receptor (ERbeta1) and the splice variant (ERbetacx/beta2) are both expressed within the human endometrium throughout the normal menstrual cycle. J. Clin. Endocrinol. Metab. 87, 5265– 5273. Curtis Hewitt, S., Goulding, E.H., Eddy, E.M., Korach, K.S., 2002. Studies using the estrogen receptor alpha knockout uterus demonstrate that implantation but not decidualization-associated signaling is estrogen dependent. Biol. Reprod. 67, 1268–1277. De Bosscher, K., Vanden Berghe, W., Haegeman, G., 2006. Cross-talk between nuclear receptors and nuclear factor kappaB. Oncogene 25, 6868–6886. Deblois, G., Hall, J.A., Perry, M.C., Laganiere, J., Ghahremani, M., Park, M., Hallett, M., Giguere, V., 2009. Genome-wide identification of direct target genes implicates estrogen-related receptor alpha as a determinant of breast cancer heterogeneity. Cancer Res. 69, 6149–6157. Deschamps, A.M., Murphy, E., Sun, J., 2010. Estrogen receptor activation and cardioprotection in ischemia reperfusion injury. Trends Cardiovasc. Med. 20, 73–78. Drummond, A.E., Britt, K.L., Dyson, M., Jones, M.E., Kerr, J.B., O’Donnell, L., Simpson, E.R., Findlay, J.K., 2002. Ovarian steroid receptors and their role in ovarian function. Mol. Cell Endocrinol. 191, 27–33. Dupont, S., Krust, A., Gansmuller, A., Dierich, A., Chambon, P., Mark, M., 2000. Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes. Development 127, 4277– 4291. Dutertre, M., Smith, C.L., 2000. Molecular mechanisms of selective estrogen receptor modulator (SERM) action. J. Pharmacol. Exp. Ther. 295, 431–437. Eddy, E.M., Washburn, T.F., Bunch, D.O., Goulding, E.H., Gladen, B.C., Lubahn, D.B., Korach, K.S., 1996. Targeted disruption of the estrogen receptor gene in male mice causes alteration of spermatogenesis and infertility. Endocrinology 137, 4796–4805. Eichner, L.J., Giguere, V., 2011. Estrogen related receptors (ERRs): a new dawn in transcriptional control of mitochondrial gene networks. Mitochondrion. 11, 544–552. Ellem, S.J., Risbridger, G.P., 2010. Aromatase and regulating the estrogen:androgen ratio in the prostate gland. J. Steroid Biochem. Mol. Biol. 118, 246–251. Enmark, E., Pelto-Huikko, M., Grandien, K., Lagercrantz, S., Lagercrantz, J., Fried, G., Nordenskjold, M., Gustafsson, J.A., 1997. Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern. J. Clin. Endocrinol. Metab. 82, 4258–4265. Flouriot, G., Brand, H., Denger, S., Metivier, R., Kos, M., Reid, G., Sonntag-Buck, V., Gannon, F., 2000. Identification of a new isoform of the human estrogen receptor-alpha (hER-alpha) that is encoded by distinct transcripts and that is able to repress hER-alpha activation function 1. EMBO J. 19, 4688–4700. Fujimoto, J., Sato, E., 2009. Clinical implication of estrogen-related receptor (ERR) expression in uterine endometrial cancers. J. Steroid Biochem. Mol. Biol. 116, 71–75. Fujimoto, J., Nakagawa, Y., Toyoki, H., Sakaguchi, H., Sato, E., Tamaya, T., 2005. Estrogen-related receptor expression in placenta throughout gestation. J. Steroid Biochem. Mol. Biol. 94, 67–69. Fujimoto, J., Alam, S.M., Jahan, I., Sato, E., Sakaguchi, H., Tamaya, T., 2007. Clinical implication of estrogen-related receptor (ERR) expression in ovarian cancers. J. Steroid Biochem. Mol. Biol. 104, 301–304. Fujimura, T., Takahashi, S., Urano, T., Ogawa, S., Ouchi, Y., Kitamura, T., Muramatsu, M., Inoue, S., 2001. Differential expression of estrogen receptor beta (ERbeta) and its C-terminal truncated splice variant ERbetacx as prognostic predictors in human prostatic cancer. Biochem. Biophys. Res. Commun. 289, 692–699. Giguere, V., 2002. To ERR in the estrogen pathway. Trends Endocrinol. Metab. 13, 220–225. Giguere, V., 2008. Transcriptional control of energy homeostasis by the estrogenrelated receptors. Endocr. Rev. 29, 677–696. Green, S., Walter, P., Kumar, V., Krust, A., Bornert, J.M., Argos, P., Chambon, P., 1986. Human oestrogen receptor cDNA: sequence, expression and homology to v-erbA. Nature 320, 134–139. Gruber, C.J., Tschugguel, W., Schneeberger, C., Huber, J.C., 2002. Production and actions of estrogens. N. Engl. J. Med. 346, 340–352. Gu, F., Hsu, H.K., Hsu, P.Y., Wu, J., Ma, Y., Parvin, J., Huang, T.H., Jin, V.X., 2010. Inference of hierarchical regulatory network of estrogen-dependent breast cancer through ChIP-based data. BMC Syst. Biol. 4, 170. Hall, J.M., McDonnell, D.P., 1999. The estrogen receptor beta-isoform (ERbeta) of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology 140, 5566–5578. Hall, J.M., Couse, J.F., Korach, K.S., 2001. The multifaceted mechanisms of estradiol and estrogen receptor signaling. J. Biol. Chem. 276, 36869–36872. Halon, A., Materna, V., Drag-Zalesinska, M., Nowak-Markwitz, E., Gansukh, T., Donizy, P., Spaczynski, M., Zabel, M., Dietel, M., Lage, H., Surowiak, P., 2011 Estrogen receptor alpha expression in ovarian cancer predicts longer overall survival. Pathol. Oncol. Res. Harris, H.A., 2007. Estrogen receptor-beta: recent lessons from in vivo studies. Mol. Endocrinol. 21, 1–13.

Harris, H.A., Katzenellenbogen, J.A., Katzenellenbogen, B.S., 2002. Characterization of the biological roles of the estrogen receptors, ERalpha and ERbeta, in estrogen target tissues in vivo through the use of an ERalpha-selective ligand. Endocrinology 143, 4172–4177. Hegele-Hartung, C., Siebel, P., Peters, O., Kosemund, D., Muller, G., Hillisch, A., Walter, A., Kraetzschmar, J., Fritzemeier, K.H., 2004. Impact of isotype-selective estrogen receptor agonists on ovarian function. Proc. Natl. Acad. Sci. USA 101, 5129–5134. Henderson, T.A., Saunders, P.T., Moffett-King, A., Groome, N.P., Critchley, H.O., 2003. Steroid receptor expression in uterine natural killer cells. J. Clin. Endocrinol. Metab. 88, 440–449. Hess, R.A., Bunick, D., Lee, K.H., Bahr, J., Taylor, J.A., Korach, K.S., Lubahn, D.B., 1997. A role for oestrogens in the male reproductive system. Nature 390, 509–512. Horne, A.W., King, A.E., Shaw, E., McDonald, S.E., Williams, A.R., Saunders, P.T., Critchley, H.O., 2009. Attenuated sex steroid receptor expression in fallopian tube of women with ectopic pregnancy. J. Clin. Endocrinol. Metab. 94, 5146– 5154. Huss, J.M., Imahashi, K., Dufour, C.R., Weinheimer, C.J., Courtois, M., Kovacs, A., Giguere, V., Murphy, E., Kelly, D.P., 2007. The nuclear receptor ERRalpha is required for the bioenergetic and functional adaptation to cardiac pressure overload. Cell. Metab. 6, 25–37. Jakimiuk, A.J., Bogusiewicz, M., Tarkowski, R., Dziduch, P., Adamiak, A., Wrobel, A., Haczynski, J., Magoffin, D.A., Jakowicki, J.A., 2004. Estrogen receptor alpha and beta expression in uterine leiomyomas from premenopausal women. Fertil. Steril. 82 (Suppl 3), 1244–1249. Jarred, R.A., McPherson, S.J., Bianco, J.J., Couse, J.F., Korach, K.S., Risbridger, G.P., 2002. Prostate phenotypes in estrogen-modulated transgenic mice. Trends Endocrinol. Metab. 13, 163–168. Kang, Y.K., Guermah, M., Yuan, C.X., Roeder, R.G., 2002. The TRAP/mediator coactivator complex interacts directly with estrogen receptors alpha and beta through the TRAP220 subunit and directly enhances estrogen receptor function in vitro. Proc. Natl. Acad. Sci. USA 99, 2642–2647. Klein-Hitpass, L., Tsai, S.Y., Greene, G.L., Clark, J.H., Tsai, M.J., O’Malley, B.W., 1989. Specific binding of estrogen receptor to the estrogen response element. Mol. Cell Biol. 9, 43–49. Kojo, H., Tajima, K., Fukagawa, M., Isogai, T., Nishimura, S., 2006. A novel estrogen receptor-related protein gamma splice variant lacking a DNA binding domain exon modulates transcriptional activity of a moderate range of nuclear receptors. J. Steroid Biochem. Mol. Biol. 98, 181–192. Kos, M., Denger, S., Reid, G., Gannon, F., 2002. Upstream open reading frames regulate the translation of the multiple mRNA variants of the estrogen receptor alpha. J. Biol. Chem. 277, 37131–37138. Kraichely, D.M., Sun, J., Katzenellenbogen, J.A., Katzenellenbogen, B.S., 2000. Conformational changes and coactivator recruitment by novel ligands for estrogen receptor-alpha and estrogen receptor-beta: correlations with biological character and distinct differences among SRC coactivator family members. Endocrinology 141, 3534–3545. Krege, J.H., Hodgin, J.B., Couse, J.F., Enmark, E., Warner, M., Mahler, J.F., Sar, M., Korach, K.S., Gustafsson, J.A., Smithies, O., 1998. Generation and reproductive phenotypes of mice lacking estrogen receptor beta. Proc. Natl. Acad. Sci. USA 95, 15677–15682. Kuiper, G.G., Enmark, E., Pelto-Huikko, M., Nilsson, S., Gustafsson, J.A., 1996. Cloning of a novel receptor expressed in rat prostate and ovary. Proc. Natl. Acad. Sci. USA 93, 5925–5930. Kuiper, G.G., Carlsson, B., Grandien, K., Enmark, E., Haggblad, J., Nilsson, S., Gustafsson, J.A., 1997. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138, 863–870. Lanvin, O., Bianco, S., Kersual, N., Chalbos, D., Vanacker, J.M., 2007. Potentiation of ICI182, 780 (Fulvestrant)-induced estrogen receptor-alpha degradation by the estrogen receptor-related receptor-alpha inverse agonist XCT790. J. Biol. Chem. 282, 28328–28334. Lee, S., Kang, D.W., Hudgins-Spivey, S., Krust, A., Lee, E.Y., Koo, Y., Cheon, Y., Gye, M.C., Chambon, P., Ko, C., 2009. Theca-specific estrogen receptor-alpha knockout mice lose fertility prematurely. Endocrinology 150, 3855–3862. Leung, Y.K., Mak, P., Hassan, S., Ho, S.M., 2006. Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling. Proc. Natl. Acad. Sci. USA 103, 13162– 13167. Leung, Y.K., Lam, H.M., Wu, S., Song, D., Levin, L., Cheng, L., Wu, C.L., Ho, S.M., 2010. Estrogen receptor beta2 and beta5 are associated with poor prognosis in prostate cancer, and promote cancer cell migration and invasion. Endocr. Relat. Cancer 17, 675–689. Levin, E.R. (2010). Minireview: extranuclear steroid receptors: roles in modulation of cell functions. Mol Endocrinol. Li, Y.F., Hu, W., Fu, S.Q., Li, J.D., Liu, J.H., Kavanagh, J.J., 2008. Aromatase inhibitors in ovarian cancer: is there a role? Int. J. Gynecol. Cancer 18, 600–614. Liu, M.M., Albanese, C., Anderson, C.M., Hilty, K., Webb, P., Uht, R.M., Price Jr., R.H., Pestell, R.G., Kushner, P.J., 2002. Opposing action of estrogen receptors alpha and beta on cyclin D1 gene expression. J. Biol. Chem. 277, 24353–24360. Lu, B., Leygue, E., Dotzlaw, H., Murphy, L.J., Murphy, L.C., 2000. Functional characteristics of a novel murine estrogen receptor-beta isoform, estrogen receptor-beta 2. J. Mol. Endocrinol. 25, 229–242. Lubahn, D.B., Moyer, J.S., Golding, T.S., Couse, J.F., Korach, K.S., Smithies, O., 1993. Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc. Natl. Acad. Sci. USA 90, 11162–11166.

D.A. Gibson, P.T.K. Saunders / Molecular and Cellular Endocrinology 348 (2012) 361–372 Luo, J., Sladek, R., Carrier, J., Bader, J.A., Richard, D., Giguere, V., 2003. Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha. Mol. Cell Biol. 23, 7947–7956. Makinen, S., Makela, S., Weihua, Z., Warner, M., Rosenlund, B., Salmi, S., Hovatta, O., Gustafsson, J.A., 2001. Localization of oestrogen receptors alpha and beta in human testis. Mol. Hum. Reprod. 7, 497–503. Malamas, M.S., Manas, E.S., McDevitt, R.E., Gunawan, I., Xu, Z.B., Collini, M.D., Miller, C.P., Dinh, T., Henderson, R.A., Keith Jr., J.C., Harris, H.A., 2004. Design and synthesis of aryl diphenolic azoles as potent and selective estrogen receptorbeta ligands. J. Med. Chem. 47, 5021–5040. Matthews, J., Gustafsson, J.A., 2003. Estrogen signaling: a subtle balance between ER alpha and ER beta. Mol. Interv. 3, 281–292. McDonnell, D.P., Clemm, D.L., Hermann, T., Goldman, M.E., Pike, J.W., 1995. Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens. Mol. Endocrinol. 9, 659–669. McInerney, E.M., Weis, K.E., Sun, J., Mosselman, S., Katzenellenbogen, B.S., 1998. Transcription activation by the human estrogen receptor subtype beta (ER beta) studied with ER beta and ER alpha receptor chimeras. Endocrinology 139, 4513– 4522. McPherson, S.J., Ellem, S.J., Simpson, E.R., Patchev, V., Fritzemeier, K.H., Risbridger, G.P., 2007. Essential role for estrogen receptor beta in stromal-epithelial regulation of prostatic hyperplasia. Endocrinology 148, 566–574. Meyers, M.J., Sun, J., Carlson, K.E., Marriner, G.A., Katzenellenbogen, B.S., Katzenellenbogen, J.A., 2001. Estrogen receptor-beta potency-selective ligands: structure–activity relationship studies of diarylpropionitriles and their acetylene and polar analogues. J. Med. Chem. 44, 4230–4251. Miao, L., Shi, J., Wang, C.Y., Zhu, Y., Du, X., Jiao, H., Mo, Z., Klocker, H., Lee, C., Zhang, J., 2010. Estrogen receptor-related receptor alpha mediates up-regulation of aromatase expression by prostaglandin E2 in prostate stromal cells. Mol. Endocrinol. 24, 1175–1186. Milne, S.A., Henderson, T.A., Kelly, R.W., Saunders, P.T., Baird, D.T., Critchley, H.O., 2005. Leukocyte populations and steroid receptor expression in human firsttrimester decidua; regulation by antiprogestin and prostaglandin E analog. J. Clin. Endocrinol. Metab. 90, 4315–4321. Moore, J.T., McKee, D.D., Slentz-Kesler, K., Moore, L.B., Jones, S.A., Horne, E.L., Su, J.L., Kliewer, S.A., Lehmann, J.M., Willson, T.M., 1998. Cloning and characterization of human estrogen receptor beta isoforms. Biochem. Biophys. Res. Commun. 247, 75–78. Morissette, M., Al Sweidi, S., Callier, S., Di Paolo, T., 2008. Estrogen and SERM neuroprotection in animal models of Parkinson’s disease. Mol. Cell Endocrinol. 290, 60–69. Nilsson, S., Makela, S., Treuter, E., Tujague, M., Thomsen, J., Andersson, G., Enmark, E., Pettersson, K., Warner, M., Gustafsson, J.A., 2001. Mechanisms of estrogen action. Physiol. Rev. 81, 1535–1565. Ogawa, S., Inoue, S., Watanabe, T., Orimo, A., Hosoi, T., Ouchi, Y., Muramatsu, M., 1998. Molecular cloning and characterization of human estrogen receptor betacx: a potential inhibitor of estrogen action in human. Nucleic Acids Res. 26, 3505–3512. Ogawa, S., Inoue, S., Watanabe, T., Hiroi, H., Orimo, A., Hosoi, T., Ouchi, Y., Muramatsu, M., 1998. The complete primary structure of human estrogen receptor beta (hER beta) and its heterodimerization with ER alpha in vivo and in vitro. Biochem. Biophys. Res. Commun. 243, 122–126. O’Lone, R., Frith, M.C., Karlsson, E.K., Hansen, U., 2004. Genomic targets of nuclear estrogen receptors. Mol. Endocrinol. 18, 1859–1875. Paech, K., Webb, P., Kuiper, G.G., Nilsson, S., Gustafsson, J., Kushner, P.J., Scanlan, T.S., 1997. Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites. Science 277, 1508–1510. Paruthiyil, S., Cvoro, A., Zhao, X., Wu, Z., Sui, Y., Staub, R.E., Baggett, S., Herber, C.B., Griffin, C., Tagliaferri, M., Harris, H.A., Cohen, I., Bjeldanes, L.F., Speed, T.P., Schaufele, F., Leitman, D.C., 2009. Drug and cell type-specific regulation of genes with different classes of estrogen receptor beta-selective agonists. PLoS One 4, e6271. Pelletier, G., El-Alfy, M., 2000. Immunocytochemical localization of estrogen receptors alpha and beta in the human reproductive organs. J. Clin. Endocrinol. Metab. 85, 4835–4840. Petersen, D.N., Tkalcevic, G.T., Koza-Taylor, P.H., Turi, T.G., Brown, T.A., 1998. Identification of estrogen receptor beta2, a functional variant of estrogen receptor beta expressed in normal rat tissues. Endocrinology 139, 1082– 1092. Pike, A.C., Brzozowski, A.M., Hubbard, R.E., Bonn, T., Thorsell, A.G., Engstrom, O., Ljunggren, J., Gustafsson, J.A., Carlquist, M., 1999. Structure of the ligandbinding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist. EMBO J. 18, 4608–4618. Ponglikitmongkol, M., Green, S., Chambon, P., 1988. Genomic organization of the human oestrogen receptor gene. Embo J. 7, 3385–3388. Poola, I., Koduri, S., Chatra, S., Clarke, R., 2000. Identification of twenty alternatively spliced estrogen receptor alpha mRNAs in breast cancer cell lines and tumors using splice targeted primer approach. J. Steroid Biochem. Mol. Biol. 72, 249– 258. Poola, I., Abraham, J., Baldwin, K., 2002. Identification of ten exon deleted ERbeta mRNAs in human ovary, breast, uterus and bone tissues: alternate splicing pattern of estrogen receptor beta mRNA is distinct from that of estrogen receptor alpha. FEBS Lett. 516, 133–138. Prins, G.S., Korach, K.S., 2008. The role of estrogens and estrogen receptors in normal prostate growth and disease. Steroids 73, 233–244.

371

Ranhotra, H.S., 2010. The estrogen-related receptor alpha: the oldest, yet an energetic orphan with robust biological functions. J. Recept. Signal Transduct. Res. 30, 193–205. Robertson, K.M., O’Donnell, L., Simpson, E.R., Jones, M.E., 2002. The phenotype of the aromatase knockout mouse reveals dietary phytoestrogens impact significantly on testis function. Endocrinology 143, 2913–2921. Routledge, E.J., White, R., Parker, M.G., Sumpter, J.P., 2000. Differential effects of xenoestrogens on coactivator recruitment by estrogen receptor (ER) alpha and ERbeta. J. Biol. Chem. 275, 35986–35993. Sakaguchi, H., Fujimoto, J., Aoki, I., Tamaya, T., 2003. Expression of estrogen receptor alpha and beta in myometrium of premenopausal and postmenopausal women. Steroids 68, 11–19. Saunders, P.T., 2005. Does estrogen receptor beta play a significant role in human reproduction? Trends Endocrinol. Metab. 16, 222–227. Saunders, P.T.K., Critchley, H.O.D., 2002. Estrogen receptor subtypes in the female reproductive tract. Reprod. Med. Rev. 10, 149–164. Saunders, P.T., Maguire, S.M., Gaughan, J., Millar, M.R., 1997. Expression of oestrogen receptor beta (ER beta) in multiple rat tissues visualised by immunohistochemistry. J. Endocrinol. 154, R13–6. Saunders, P.T., Millar, M.R., Williams, K., Macpherson, S., Harkiss, D., Anderson, R.A., Orr, B., Groome, N.P., Scobie, G., Fraser, H.M., 2000. Differential expression of estrogen receptor-alpha and -beta and androgen receptor in the ovaries of marmosets and humans. Biol. Reprod. 63, 1098–1105. Saunders, P.T., Sharpe, R.M., Williams, K., Macpherson, S., Urquart, H., Irvine, D.S., Millar, M.R., 2001. Differential expression of oestrogen receptor alpha and beta proteins in the testes and male reproductive system of human and non-human primates. Mol. Hum. Reprod. 7, 227–236. Saunders, P.T., Millar, M.R., Macpherson, S., Irvine, D.S., Groome, N.P., Evans, L.R., Sharpe, R.M., Scobie, G.A., 2002. ERbeta1 and the ERbeta2 splice variant (ERbetacx/beta2) are expressed in distinct cell populations in the adult human testis. J. Clin. Endocrinol. Metab. 87, 2706–2715. Saville, B., Wormke, M., Wang, F., Nguyen, T., Enmark, E., Kuiper, G., Gustafsson, J.A., Safe, S., 2000. Ligand-, cell-, and estrogen receptor subtype (alpha/beta)dependent activation at GC-rich (Sp1) promoter elements. J. Biol. Chem. 275, 5379–5387. Scobie, G.A., Macpherson, S., Millar, M.R., Groome, N.P., Romana, P.G., Saunders, P.T., 2002. Human oestrogen receptors: differential expression of ER alpha and beta and the identification of ER beta variants. Steroids 67, 985–992. Sierens, J.E., Scobie, G.A., Wilson, J., Saunders, P.T., 2004. Cloning of oestrogen receptor beta from Old and New World primates: identification of splice variants and functional analysis. J. Mol. Endocrinol. 32, 703–718. Sierens, J.E., Sneddon, S.F., Collins, F., Millar, M.R., Saunders, P.T., 2005. Estrogens in testis biology. Ann. N Y Acad. Sci. 1061, 65–76. Sladek, R., Bader, J.A., Giguere, V., 1997. The orphan nuclear receptor estrogenrelated receptor alpha is a transcriptional regulator of the human mediumchain acyl coenzyme A dehydrogenase gene. Mol. Cell Biol. 17, 5400–5409. Springwald, A., Lattrich, C., Skrzypczak, M., Goerse, R., Ortmann, O., Treeck, O., 2010. Identification of novel transcript variants of estrogen receptor alpha, beta and progesterone receptor gene in human endometrium. Endocrine 37, 415–424. Stauffer, S.R., Coletta, C.J., Tedesco, R., Nishiguchi, G., Carlson, K., Sun, J., Katzenellenbogen, B.S., Katzenellenbogen, J.A., 2000. Pyrazole ligands: structure-affinity/activity relationships and estrogen receptor-alpha-selective agonists. J. Med. Chem. 43, 4934–4947. Stygar, D., Wang, H., Vladic, Y.S., Ekman, G., Eriksson, H., Sahlin, L., 2001. Colocalization of oestrogen receptor beta and leukocyte markers in the human cervix. Mol. Hum. Reprod. 7, 881–886. Sun, J., Meyers, M.J., Fink, B.E., Rajendran, R., Katzenellenbogen, J.A., Katzenellenbogen, B.S., 1999. Novel ligands that function as selective estrogens or antiestrogens for estrogen receptor-alpha or estrogen receptorbeta. Endocrinology 140, 800–804. Sun, J., Huang, Y.R., Harrington, W.R., Sheng, S., Katzenellenbogen, J.A., Katzenellenbogen, B.S., 2002. Antagonists selective for estrogen receptor alpha. Endocrinology 143, 941–947. Tanenbaum, D.M., Wang, Y., Williams, S.P., Sigler, P.B., 1998. Crystallographic comparison of the estrogen and progesterone receptor’s ligand binding domains. Proc. Natl. Acad. Sci. USA 95, 5998–6003. Taylor, A.H., Al-Azzawi, F., 2000. Immunolocalisation of oestrogen receptor beta in human tissues. J. Mol. Endocrinol. 24, 145–155. Teyssier, C., Bianco, S., Lanvin, O., Vanacker, J.M., 2008. The orphan receptor ERRalpha interferes with steroid signaling. Nucleic Acids Res. 36, 5350–5361. Thornton, J.W., 2001. Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. Proc. Natl. Acad. Sci. USA 98, 5671–5676. Tremblay, A.M., Giguere, V., 2007. The NR3B subgroup: an overview. Nucl. Recept. Signal. 5, e009. Turner, K.J., Macpherson, S., Millar, M.R., McNeilly, A.S., Williams, K., Cranfield, M., Groome, N.P., Sharpe, R.M., Fraser, H.M., Saunders, P.T., 2002. Development and validation of a new monoclonal antibody to mammalian aromatase. J. Endocrinol. 172, 21–30. Vanacker, J.M., Bonnelye, E., Delmarre, C., Laudet, V., 1998. Activation of the thyroid hormone receptor alpha gene promoter by the orphan nuclear receptor ERR alpha. Oncogene 17, 2429–2435. Vanacker, J.M., Pettersson, K., Gustafsson, J.A., Laudet, V., 1999. Transcriptional targets shared by estrogen receptor-related receptors (ERRs) and estrogen receptor (ER) alpha, but not by ERbeta. EMBO J. 18, 4270–4279.

372

D.A. Gibson, P.T.K. Saunders / Molecular and Cellular Endocrinology 348 (2012) 361–372

Wakeling, A.E., Dukes, M., Bowler, J., 1991. A potent specific pure antiestrogen with clinical potential. Cancer Res. 51, 3867–3873. Wallace, A.E., Gibson, D.A., Saunders, P.T., Jabbour, H.N., 2010. Inflammatory events in endometrial adenocarcinoma. J. Endocrinol. 206, 141–157. Wang, H., Stjernholm, Y., Ekman, G., Eriksson, H., Sahlin, L., 2001. Different regulation of oestrogen receptors alpha and beta in the human cervix at term pregnancy. Mol. Hum. Reprod. 7, 293–300. Wang, Z., Zhang, X., Shen, P., Loggie, B.W., Chang, Y., Deuel, T.F., 2005. Identification, cloning, and expression of human estrogen receptor-alpha36, a novel variant of human estrogen receptor-alpha66. Biochem. Biophys. Res. Commun. 336, 1023–1027. Weihua, Z., Warner, M., Gustafsson, J.A., 2002. Estrogen receptor beta in the prostate. Mol. Cell Endocrinol. 193, 1–5. Welboren, W.J., Stunnenberg, H.G., Sweep, F.C., Span, P.N., 2007. Identifying estrogen receptor target genes. Mol. Oncol. 1, 138–143. Winuthayanon, W., Hewitt, S.C., Orvis, G.D., Behringer, R.R., Korach, K.S., 2010. Uterine epithelial estrogen receptor alpha is dispensable for proliferation but

essential for complete biological and biochemical responses. Proc. Natl. Acad. Sci. USA 107, 19272–19277. Wong, N.A., Malcomson, R.D., Jodrell, D.I., Groome, N.P., Harrison, D.J., Saunders, P.T., 2005. ERbeta isoform expression in colorectal carcinoma: an in vivo and in vitro study of clinicopathological and molecular correlates. J. Pathol. 207, 53–60. Yu, D.D., Forman, B.M., 2005. Identification of an agonist ligand for estrogen-related receptors ERRbeta/gamma. Bioorg. Med. Chem. Lett. 15, 1311–1313. Zhou, W., Liu, Z., Wu, J., Liu, J.H., Hyder, S.M., Antoniou, E., Lubahn, D.B., 2006. Identification and characterization of two novel splicing isoforms of human estrogen-related receptor beta. J. Clin. Endocrinol. Metab. 91, 569–579. Zhou, W., Lo, S.C., Liu, J.H., Hannink, M., Lubahn, D.B., 2007. ERRbeta: a potent inhibitor of Nrf2 transcriptional activity. Mol. Cell Endocrinol. 278, 52–62. Zuercher, W.J., Gaillard, S., Orband-Miller, L.A., Chao, E.Y., Shearer, B.G., Jones, D.G., Miller, A.B., Collins, J.L., McDonnell, D.P., Willson, T.M., 2005. Identification and structure–activity relationship of phenolic acyl hydrazones as selective agonists for the estrogen-related orphan nuclear receptors ERRbeta and ERRgamma. J. Med. Chem. 48, 3107–3109.