2014

http://informahealthcare.com/rstISSN: 1079-9893 (print), 1532-4281 (electronic)

J Recept Signal Transduct Res, 2014; 34(1): 1–5! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10799893.2013.853188

REVIEW ARTICLE

Estrogen receptors (ERa versus ERb): friends or foes in human biology?

Sonia Lobo Planey, Raj Kumar, and John A. Arnott

Department of Basic Sciences, The Commonwealth Medical College, Scranton, PA, USA

Abstract

Most of the biological effects of estrogens are mediated via the estrogen receptors (ERs) at thelevel of gene regulation. Recently, new information regarding the role of ERs in physiology,pathology and the mechanisms through which estrogens bring about these functions hasemerged. The physiological effects of estrogen are manifested through two ER isoforms – ERa

and ERb – which display distinct regions of sequence homology. The crystal structures of thesereceptors bound to their specific ligands (e.g. agonists or antagonists) have revealed muchabout how ligand binding alters receptor structure/conformation and the interaction withcoactivators or corepressors as well as how it determines the cellular response to a ligand.ERs are involved in the variety of physiological and pathological activities and different cellsand tissues have shown divergent responses to these two receptor isoforms. The discoveryof sub-isoforms of ER alpha and beta has further complicated our understanding of howthe interaction between ERs and its ligands contribute to the development of disease.Nevertheless, continuing efforts in the study of ERs have helped us to more clearly define theirrole in disease and to develop novel, ER-targeted therapeutics.

Keywords

Coregulators, estrogen receptor, generegulation, pathology, physiology

History

Received 5 June 2013Revised 3 October 2013Accepted 5 October 2013Published online 4 November 2013

Introduction

The estrogen receptors (ERs) are ligand-inducible, intracel-

lular transcription factors, belonging to the nuclear receptor

superfamily. Estrogen biology is exceedingly complex and

important in the development and function of numerous

tissue/cell physiologies (1–3). Most of the biological effects

of estrogens are mediated by ERs which up- or downregulate

the expression of their target genes via binding to site-specific

DNA (estrogen response element [ERE]) sequences and/or

specific coregulatory proteins including coactivators and

corepressors (Figure 1) (4–6). Coactivators turn on target

gene transcription, while negative coregulators and corepres-

sors inhibit gene activation and also turn off activated target

genes. ERs can associate with distinct subsets of cofactors

depending on their binding affinities and the relative abun-

dance of these factors. These binding events result in cross-

communication with the transcription modulators and

recruitment of the general transcription machinery (7). In

recent years, new information regarding the actions of ERs

has emerged (8–10).

For a long time, it was generally accepted that there was

only one ER gene coding for ERa, which bound estrogen with

high affinity. However, in the mid-1990s, the discovery of a

new gene encoding a second type of ER called ERb (11)

caused a paradigm shift in our understanding of the estrogen

signaling system. The locations of the ER� and ER� genes in

the human chromosome indicate that these are two independ-

ent genes (11). Further, the distribution and expression of

these two forms in estrogen-sensitive tissues (11–15) has

added to the complexity of the tissue response to estrogens.

Because of the importance of ERs in numerous diseases and

the unwanted side effects of classical antagonists, there has

been an increasing focus towards developing selective estro-

gen receptor modulators (SERMs). SERMs are a class of

compounds that act on the ERs, yet distinguish themselves

from pure receptor agonists and antagonists because their

action is tissue-specific. This allows for selective inhibition or

stimulation of estrogen-like action in various tissues. This also

raises the possibility that any selective effect of estrogen could

be due to the differential expression of these two ER genes,

depending on the physiological and/or pathological state of

the target tissues. Indeed, there are numerous examples in the

literature supporting this notion. In this review article, we

discuss the current knowledge concerning the biological

functions of the ERs in the human physiology and pathology.

The dynamic structure of the ERs

Like other members of the nuclear hormone receptor family,

the ERs also possess a modular structure and are composed of

three major functional domains that serve specific roles (16)

(Figure 2). These are the N-terminal domain (NTD), the DNA

binding domain (DBD), and the ligand binding domain

(LBD). Full transcriptional activity of the ERs is thought to be

Address for correspondence: John A. Arnott, Department of BasicSciences, The Commonwealth Medical College, 525 Pine Street,Scranton, PA 18509, USA. Tel: +570-504-9675. Fax: +570-504-9660.E-mail: jarnott@tcmedc.org

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achieved by synergism between the two activation function

(AF) domains, AF1 and AF2, located within the NTD and

LBD, respectively. The activity of the AFs is dependent upon

the specific promoter and cell/tissue (17,18). AF1 functions

in a hormone-independent manner, whereas AF2 function

requires the presence of a ligand (19). In terms of sequence

homology, ERb shows a high homology to ERa in the DBD

and in the LBD (14,15); however, the NTD of ERb is shorter

than that of ERa with very poor sequence homology to that

of ERa. In addition to the NTD, DBD, and LBD, the ERs

consist of ‘‘hinge and F’’ regions. The ‘‘hinge’’ region

contains a nuclear localization signal (NLS) and serves as a

flexible region connecting the DBD and LBD. The ‘‘F’’

region, which contains 42 amino acids, is located towards the

C-terminal end of the LBD and possesses specific modulation

capabilities of gene transcription in a ligand-, promoter-, and

tissue-specific manner (20–22). The three-dimensional (3D)

structures of the independently expressed DBD and LBD have

been solved and show overall folds that represent globular

proteins with natively-ordered conformations (23–26). To

date, no 3D, natively-folded structure for the NTD is available

for the ERs. The DBD of both ERa and ERb isoforms usually

binds to the ERE which is composed of a palindromic

hexanucleotide 50AGGTCAnnnTGACCT3’. The 3D structure

of ERa showed the DBD:ERE interactions and indicated that

the ERE facilitated dimerization through the P box and D box

sequences in the Zinc finger domains (23,24).

The ER LBD structure consists of 12 helices, contains

a hormone binding pocket, and is responsible primarily for

functions activated by ligand binding, such as coregulator

binding to AF2 and receptor dimerization (27). The crystal

structure of 17b-estradiol (E2)-bound ERa LBD showed that

in a compact ellipsoid cavity, E2 is buried in a highly

hydrophobic environment (25). The crystal structures of the

(E2)-bound ERb assert the importance of a hydrogen bond

network on the opposite sides of the respective ligands

(28,29). The specificity of the ligand association between ERa

and ERb may stem from the distinction in the residues lining

the binding pocket (30). The crystal structure of the complex

of ERa LBD bound to non-steroidal ligands shows that the

hydrophobic interactions primarily govern the accommoda-

tion of distinct LBD structures (31). Numerous compounds

that are known to possess estrogenic activity have been

shown to interact with the ER, the intrinsic ERa and ERb LBD

Figure 1. A model for the regulation of transcription by ER–cofactor assemblies. Both AF1 and AF2 regions recruit certain specific cofactors. A bridgeis formed between AF1 and AF2 through these and/or other cofactor(s). AF1 and AF2 can also interact directly. The bound cofactor(s) are determinedby their levels in particular cell types. The complex alters local chromatin structure, e.g. by catalyzing histone acetylation or deacetylation and affectsthe stabilization of the transcription pre-initiation complex (TATA-box-binding protein (TBP)–TBP-associated factors (TAFs)–RNA polymerase II(RNA Pol II)). The receptor complex, bound to DNA enhancer sites, thus recruits and regulates polymerase II via accumulations of specific proteins,which make a functional bridge between the receptor and polymerase II. The activity of kinases and phosphatases regulating signaling pathways alsocontribute to this process by altering the state of phosphorylation of both receptor and cofactors (not shown). The receptor–cofactor assembly may alsointeract directly with the basal transcription machinery at the TBP/TATA box to regulate transcription. Different colors and shapes show the cofactorproteins. Precise relationships and sites of these cofactor proteins are not accurate and may differ in different ERs.

Figure 2. The sequence organization of the two isoforms of estrogen receptors, ERa (upper panel) and ERb (lower panel). Different domains arehighlighted: NTD – (amino terminal domain) in red; DBD (DNA binding domain); hinge region in blue; LBD (ligand binding domain); and F regionlocated towards the C-terminal. Amino acid sequence position is given for each domain. The precise location of the AF1 and AF2 within the NTD andLBD, respectively, is not defined. The letters A–F represent, NTD (A/B), DBD (C), Hinge (D), LBD (E) and F (F), respectively.

2 S. L. Planey et al. J Recept Signal Transduct Res, 2014; 34(1): 1–5

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(32–34) and several synthetic ligands to ERa have been

developed (35).

To date, relatively little information exists on the structure

of the NTD of the ERs. Secondary structural analyses

concluded that both ERa and ERb NTDs are unstructured

in solution (36). Further, when the ERa NTD was bound to

the TATA box binding protein (TBP), structural changes

were induced in ERa NTD (36). On the other hand, TBP fails

to bind to ERb under similar conditions. These observed

differences in binding of TBP to the NTD of ERa and ERb

supports a model where the two receptor isoforms may be

utilizing different sets of target binding proteins (37,38). This

is consistent with reports of functional differences between

the ERa NTD and ERb NTD which show that the ERa AF1

domain can function in an autonomous manner, whereas

the AF1 function of ERb cannot (36). It has also been

reported that under most conditions ERb possesses a weaker

transactivational potency compared to ERa (3), and these

differences appear to be cell- and promoter-specific (3).

The biology and pathology of ERs in different tissues

The search for improved ERa- and ERb-, and/or tissue-

specific SERM ligands that can provide the benefits of

estrogens and avoid unwanted side effects of E2 have

revolutionized the clinical applicability of targeting estrogen

signaling to include prevention or treatment of menopausal

symptoms, osteoporosis, cardiovascular disease, breast cancer

and other estrogen-related indications (39,40). For example,

some of the ERa-selective ligands have been found to possess

much higher agonist potency for ERa than for ERb or show

full ERa agonism but pure ERb antagonism (33). Since AF2

in both ERa and ERb shares similar structural homology, it is

logical to raise the question whether these differences pertain

to contacting of the ligand-bound ERa and ERb with different

sets of coactivators, corepressors, or other cofactors. Indeed,

there are examples where the affinity of the ERa interaction

with a specific coactivator is much higher than that observed

for the ERb (41); moreover, in contrast to ERa, ERb appears

to interact with another coactivator in a ligand-independent

manner (42). Thus, one could speculate that preferential

binding of certain coactivators to one of the ERs must have

consequences for estrogen signaling. In fact, overexpression

of certain ER coactivators has been observed in breast and

ovarian cancers (43). There are also suggestions that changes

in the expression levels of classical corepressors, which

associate with antagonist-bound ERs, may contribute to the so

called ‘‘tamoxifen resistance’’ in breast cancer treatment.

It will be interesting to determine how the expression of ERa

and ERb correlates with an imbalance or changes in the ratio

between corepressors and coactivators under these disease

conditions, and whether such changes shift the balance from

differentiation to proliferation and thereby contributing to

the development of diseases. Historically the mechanism

of action of estrogen due to the contributions of either

ERa and/or ERb to have been difficult to determine even

in tissues like prostate, ovary and lung where ERb

is expressed at high levels and ERa at low levels (44). An

even more complex scenario for studying estrogen action

exists in mammary gland, bone, uterus, central nervous

system and cardiovascular systems where both ERa and ERb

show significant expression and additionally influence each

other’s functions (3,45,46). In testes and mammary glands,

both the ERa and ERb are expressed, but their cellular

distribution is distinct. For example, in mammary glands, ERb

is mostly present in epithelial cell nuclei. In testis ERa is

reported to be localized in the nuclei of the Leydig cells,

while ERb is found in germ cells, Sertoli cells, and fetal

Leydig cells (47). Due to their crucial role in the maintenance

of bone mass in females, estrogens play important roles in

bone metabolism and homeostasis as is evident from the rapid

loss of trabecular bone and development of osteoporosis that

occurs after ovariectomy or throughout menopause (47–49).

Since, suppression of osteoclastic bone resorption and stimu-

lation of osteoblastic bone formation form the basis for the

bone-preserving effects of estrogens, it raises the question

whether both ERa and ERb differ in their cellular localization

and/or functions in bone. Both ERa and ERb have been

detected in osteoblasts and osteocytes in bone tissue and in

chondrocytes in the epiphysial growth plates, suggesting

that both ERa and ERb have overlapping distribution in cells

of the osteoblastic and chondrocytic lineages (47,50–54).

There are findings to suggest that ERa mediates the growth-

promoting effects of E2 but is not involved in maintenance

of trabecular bone; whereas the major role of ERb during

pubertal growth is to terminate the growth spurt in females,

limiting longitudinal and radial bone growth. Therefore,

a normally functioning ERb may be responsible for the shorter

bones and lower peak bone mass normally in females.

Tissue/cell selectively targeting of ER subtypesfor treatments

The therapeutic potential of ERa has been utilized for decades

yet, the real therapeutic value of ERb is still under debate.

For example, the clinical uses of SERMs and selective

estrogen receptor down-regulators (SERDs) such as fulves-

trant are mainly based on their effects on ERa, and thereby

not necessarily displaying ER-subtype selectivity (55,56).

Tissue selectivity of SERMs is mostly determined by changes

in the conformational dynamics of the ER that may alter

ER-coregulator recruitment (57), but the exact mechanisms

that determine tissue selectivity are unclear, and it is difficult

to predict the tissue specific effects SERMs may elicit on

two ER-subtypes. Due to the structural features of ERaand ERb, it has been challenging to identify ERb selective

ligands with high selectivity, potency, and binding affinity.

Thus, developing selective ERb ligands has been a field of

active research in recent years. Several approaches including

high throughput screening have been used to identify new

ERb selective ligands, which exhibit at least one or more

structural features that contribute to increased affinity and

selectivity for ERb with minimal induction of ERa activity

(58). Though the development of such ligands has proved

challenging due to the similarities of ERa and ERb LBD

structures, subtle differences in the size and amino acids

lining the LBD pocket may allow generation of subtype

selective SERMs. Both subtype selectivity and tissue select-

ivity must be optimized in order to effectively target ER

signaling for endocrine-based therapies. When viewing ERs

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as therapeutic targets, the major challenge is how to

selectively control this cell/tissue and gene specificity in a

manner that affects only deleterious actions of ERs in

diseased tissues without altering essential normal functions.

However, for pharmaceutical purposes, it makes sense to

investigate the possibility of identifying ER subtype specific

modulators that act outside of the ligand-binding pocket,

which could complement or replace existing SERMs by

influencing the conformational dynamics coupled with allo-

steric regulations of the ERs. It is intellectually satisfying

to hypothesize that such allosteric regulations could stabilize

a specific conformer that reduces the affinity of the second

binding site for its ligand, and this dynamics could be

explored as novel drug target to produce ER subtype specific

differential responses.

Summary and perspectives

A myriad of physiological processes in mammals are

influenced by estrogens and their receptors, ERa and ERb.

Given their widespread role in normal human physiology,

it is not surprising that ERa and ERb are implicated in the

development or progression of a number of diseases. ERa and

ERb can regulate different set of genes in a tissue- and cell-

specific manner. Even within the same tissue, ERa and ERb

have been shown to differentially regulate gene expression.

Because ERa and ERb differentially regulate gene expression,

differences in the expression or activity of ERa and ERb could

have profound effects on gene expression. These receptors

can differentially regulate transcription; thus depending on

the relative levels of receptors, estrogen can increase,

decrease or have no effect on transcription. The changes in

the level and/or activity of different ERs are reported to occur

with age and disease, and such changes would have profound

effects on gene expression in the cell. Further, ER signaling

depends on coregulators. Thus, by altering expression levels

of coregulators and/or post translational modifications of

ER and/or the coregulators, estrogen can evoke different

cellular responses. It is not yet clear whether unique tissue/

cell-specific coregulatory protein interactions can fully

explain the tissue/cell-specific actions of the ERs. The LBD

crystal structures have clearly demonstrated that differing

sets of coactivators/corepressors come together in response to

agonist or antagonist ligand binding such that an agonist

in one cell type can be an antagonist in another cell type.

The overall picture is one of a complex, dynamic network

controlled by the two ERs. Beyond endogenous estrogens,

treatments with SERMs for ERa and ERb are also capable

of providing disease protection. Indeed, pharmacological

activation or inhibition of ERa and/or ERb has already

provided a basis for many therapeutic interventions. However,

the use of these SERMs has also yielded undesired effects.

Thus, an important challenge that remains is to uncouple the

beneficial actions from other deleterious ones. In addition,

we have yet to answer several key questions regarding ER

signaling in specific tissues with respect to age and sex and

under certain physiological and pathological conditions.

Indeed, a more thorough understanding of the ERs would

foster the identification of new markers for prognosis or

prediction of response to endocrine therapy as well as

promote novel therapeutic strategies that incorporate novel

SERMs with target specific effects.

Declaration of interest

The authors report no declarations of interest.

References

1. Muramatsu M, Inoue S. Estrogen receptors: how do they controlreproductive and nonreproductive functions? Biochem Biophys ResCommun 2000;270:1–10

2. Lumachi F, Luisetto G, Basso SM, et al. Endocrine therapy ofbreast cancer. Curr Med Chem 2011;18:513–22.

3. Nilsson S, Gustafsson JA. Estrogen receptors: therapies targetedto receptor subtypes. Clin Pharmacol Ther 2011;89:44–55.

4. Gronemeyer H. Transcription activation by estrogen and proges-terone receptors. Annu Rev Genet 1991;25:89–123.

5. Kumar R, Thompson EB. The structure of the nuclear hormonereceptors. Steroids 1999;64:310–9.

6. Parker MG. Transcriptional activation by oestrogen receptors.Biochem Soc Symp 1998;63:45–50.

7. Smith CL, O’Malley BW. Coregulator function: a key to under-standing tissue specificity of selective receptor modulators.Endocr Rev 2004;25:45–71.

8. Karamouzis MV, Konstantinopoulos PA, Badra FA, PapavassiliouAG. SUMO and estrogen receptors in breast cancer. Breast CancerRes Treat 2008;107:195–210.

9. Swedenborg E, Power KA, Cai W, et al. Regulation of estrogenreceptor beta activity and implications in health and disease.Cell Mol Life Sci 2009;66:3873–94.

10. Welboren WJ, Sweep FC, Span PN, Stunnenberg HG. Genomicactions of estrogen receptor alpha: what are the targets and how arethey regulated? Endocr Relat Cancer 2009;16:1073–89

11. Enmark E, Pelto-Huikko M, Grandien K, et al. Human estro-gen receptor beta-gene structure, chromosomal localization, andexpression pattern. J Clin Endocrinol Metab 1997;82:4258–65.

12. Katzenellenbogen BS, Korach KS. A new actor in the estrogenreceptor drama–enter ER-beta. Endocrinology 1997;138:861–2.

13. Kuiper GG, Carlsson B, Grandien K, et al. Comparison of theligand binding specificity and transcript tissue distribution ofestrogen receptors alpha and beta. Endocrinology 1997;138:863–70.

14. Kuiper GG, Enmark E, Pelto-Huikko M, et al. Cloning of a novelreceptor expressed in rat prostate and ovary. Proc Natl Acad Sci U SA 1996;93:5925–30.

15. Mosselman S, Polman J, Dijkema R. ER beta: identification andcharacterization of a novel human estrogen receptor. FEBS Lett1996;392:49–53.

16. Beato M, Herrlich P, Schutz G. Steroid hormone receptors: manyactors in search of a plot. Cell 1995;83:851–7.

17. Beato M. Gene regulation by steroid hormones. Cell 1989;56:335–44.

18. Tora L, White J, Brou C, et al. The human estrogen receptor hastwo independent nonacidic transcriptional activation functions. Cell1989;59:477–87.

19. Berry M, Metzger D, Chambon P. Role of the twoactivating domains of the oestrogen receptor in the cell-type andpromoter-context dependent agonistic activity of the anti-oestrogen4-hydroxytamoxifen. EMBO J 1990;9:2811–8.

20. Montano MM, Muller V, Trobaugh A, Katzenellenbogen BS.The carboxy-terminal F domain of the human estrogen receptor:role in the transcriptional activity of the receptor and the effective-ness of antiestrogens as estrogen antagonists. Mol Endocrinol 1995;9:814–25.

21. Koide A, Zhao C, Naganuma M, et al. Identification of regionswithin the F domain of the human estrogen receptor alpha that areimportant for modulating transactivation and protein-protein inter-actions. Mol Endocrinol 2007;21:829–42.

22. Yang J, Singleton DW, Shaughnessy EA, Khan SA. The F-domainof estrogen receptor-alpha inhibits ligand induced receptor dimer-ization. Mol Cell Endocrinol 2008;295:94–100.

23. Schwabe JW, Neuhaus D, Rhodes D. Solution structure of theDNA-binding domain of the oestrogen receptor. Nature 1990;348:458–61.

4 S. L. Planey et al. J Recept Signal Transduct Res, 2014; 34(1): 1–5

Jour

nal o

f R

ecep

tors

and

Sig

nal T

rans

duct

ion

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Ond

okuz

May

is U

niv.

on

04/2

3/14

For

pers

onal

use

onl

y.

24. Schwabe JW, Chapman L, Finch JT, Rhodes D. The crystalstructure of the estrogen receptor DNA-binding domain bound toDNA: how receptors discriminate between their response elements.Cell 1993;75:567–78.

25. Brzozowski AM, Pike AC, Dauter Z, et al. Molecular basis ofagonism and antagonism in the oestrogen receptor. Nature 1997;389:753–8.

26. Pike AC, Brzozowski AM, Hubbard RE, et al. Structure of theligand-binding domain of oestrogen receptor beta in the presence ofa partial agonist and a full antagonist. EMBO J 1999;18:4608–18.

27. Kong EH, Heldring N, Gustafsson JA, et al. Delineation of a uniqueprotein-protein interaction site on the surface of the estrogenreceptor. Proc Natl Acad Sci U S A 2005;102:3593–8.

28. Tanenbaum DM, Wang Y, Williams SP, Sigler PB. Crystallographiccomparison of the estrogen and progesterone receptor’s ligandbinding domains. Proc Natl Acad Sci U S A 1998;95:5998–6003.

29. Celik L, Lund JD, Schiott B. Conformational dynamics of theestrogen receptor alpha: molecular dynamics simulations of theinfluence of binding site structure on protein dynamics.Biochemistry 2007;46:1743–58.

30. Anstead GM, Carlson KE, Katzenellenbogen JA. The estradiolpharmacophore: ligand structure-estrogen receptor binding affinityrelationships and a model for the receptor binding site. Steroids1997;62:268–303.

31. Shiau AK, Barstad D, Loria PM, et al. The structural basis ofestrogen receptor/coactivator recognition and the antagonism ofthis interaction by tamoxifen. Cell 1998;95:927–37.

32. Katzenellenbogen BS, Choi I, Delage-Mourroux R, et al. Molecularmechanisms of estrogen action: selective ligands and receptorpharmacology. J Steroid Biochem Mol Biol 2000;74:279–85.

33. Sun J, Meyers MJ, Fink BE, et al. Novel ligands that function asselective estrogens or antiestrogens for estrogen receptor-alpha orestrogen receptor-beta. Endocrinology 1999;140:800–4.

34. Edsall Jr RJ, Harris HA, Manas ES, Mewshaw RE. ERbetaligands. Part 1: the discovery of ERbeta selective ligands whichembrace the 4-hydroxy-biphenyl template. Bioorg Med Chem2003;11:3457–74.

35. Shang Y. Molecular mechanisms of oestrogen and SERMs inendometrial carcinogenesis. Nat Rev Cancer 2006;6:360–8.

36. Warnmark A, Wikstrom A, Wright AP, et al. The N-terminal regionsof estrogen receptor alpha and beta are unstructured in vitro andshow different TBP binding properties. J Biol Chem 2001;276:45939–44.

37. Kumar R, Lee JC, Bolen DW, Thompson EB. The conformationof the glucocorticoid receptor af1/tau1 domain induced byosmolyte binds co-regulatory proteins. J Biol Chem 2001;276:18146–52.

38. Kumar R, Thompson EB. Transactivation functions of theN-terminal domains of nuclear hormone receptors: protein foldingand coactivator interactions. Mol Endocrinol 2003;17:1–10.

39. Compston JE. Selective oestrogen receptor modulators: potentialtherapeutic applications. Clin Endocrinol (Oxf) 1998;48:389–91.

40. Gustafsson JA. Therapeutic potential of selective estrogen receptormodulators. Curr Opin Chem Biol 1998;2:508–11.

41. Suen CS, Berrodin TJ, Mastroeni R, et al. A transcriptionalcoactivator, steroid receptor coactivator-3, selectively augmentssteroid receptor transcriptional activity. J Biol Chem 1998;273:27645–53.

42. Tremblay A, Tremblay GB, Labrie F, Giguere V. Ligand-inde-pendent recruitment of SRC-1 to estrogen receptor beta throughphosphorylation of activation function AF-1. Mol Cell 1999;3:513–9.

43. Anzick SL, Kononen J, Walker RL, et al. AIB1, a steroid receptorcoactivator amplified in breast and ovarian cancer. Science 1997;277:965–8.

44. Krege JH, Hodgin JB, Couse JF, et al. Generation and reproductivephenotypes of mice lacking estrogen receptor beta. Proc Natl AcadSci U S A 1998;95:15677–82.

45. Warner M, Nilsson S, Gustafsson JA. The estrogen receptor family.Curr Opin Obstet Gynecol 1999;11:249–54.

46. Nilsson S, Koehler KF, Gustafsson JA. Development of subtype-selective oestrogen receptor-based therapeutics. Nat Rev DrugDiscov 2011;10:778–92.

47. Nilsson S, Makela S, Treuter E, et al. Mechanisms of estrogenaction. Physiol Rev 2001;81:1535–65.

48. Turner RT. Mice, estrogen, and postmenopausal osteoporosis.J Bone Miner Res 1999;14:187–91.

49. Turner RT, Wakley GK, Hannon KS. Differential effects ofandrogens on cortical bone histomorphometry in gonadectomizedmale and female rats. J Orthop Res 1990;8:612–7.

50. Onoe Y, Miyaura C, Ohta H, et al. Expression of estrogen receptorbeta in rat bone. Endocrinology 1997;138:4509–12.

51. Oreffo RO, Kusec V, Virdi AS, et al. Expression of estrogenreceptor-alpha in cells of the osteoclastic lineage. Histochem CellBiol 1999;111:125–33.

52. Kusec V, Virdi AS, Prince R, Triffitt JT. Localization of estrogenreceptor-alpha in human and rabbit skeletal tissues. J ClinEndocrinol Metab 1998;83:2421–8.

53. Nilsson LO, Boman A, Savendahl L, et al. Demonstration ofestrogen receptor-beta immunoreactivity in human growth platecartilage. J Clin Endocrinol Metab 1999;84:370–3.

54. Vidal O, Kindblom LG, Ohlsson C. Expression and localization ofestrogen receptor-beta in murine and human bone. J Bone MinerRes 1999;14:923–9.

55. Shapiro DJ, Mao C, Cherian MT. Small molecule inhibitors asprobes for estrogen and androgen receptor action. J Biol Chem2011;286:4043–8.

56. Robertson JF. Fulvestrant (Faslodex�) – How to make a good drugbetter. Oncologist 2007;12:774–84.

57. Lonard DM, O’Malley BW. Nuclear receptor coregulators: modu-lators of pathology and therapeutic targets. Nat Rev Endocrinol2012;8:598–604.

58. Nilsson S, Koehler KF, Gustafsson JA. Development of subtype-selective oestrogen receptor-based therapeutics. Nat Rev DrugDiscov 2011;10:778–92.

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