Review Article Sex Hormone Receptor Repertoire in Breast...

Hindawi Publishing CorporationInternational Journal of Breast CancerVolume 2013 Article ID 284036 14 pageshttpdxdoiorg1011552013284036

Review ArticleSex Hormone Receptor Repertoire in Breast Cancer

Gerald M Higa12 and Ryan G Fell3

1 Schools of Pharmacy and Medicine West Virginia University Morgantown WV 26506 USA2 Robert C Byrd Health Sciences Center West Virginia University One Medical Center Drive PO Box 9520 MorgantownWV 26506 USA

3 School of Pharmacy West Virginia University Morgantown WV 26506 USA

Correspondence should be addressed to Gerald M Higa ghigahscwvuedu

Received 17 July 2013 Revised 7 September 2013 Accepted 10 September 2013

Academic Editor Bent Ejlertsen

Copyright copy 2013 G M Higa and R G Fell This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Classification of breast cancer as endocrine sensitive hormone dependent or estrogen receptor (ER) positive refers singularly toER120572 One of the oldest recognized tumor targets disruption of ER120572-mediated signaling is believed to be the mechanistic mode ofaction for all hormonal interventions used in treating this disease Whereas ER120572 is widely accepted as the single most importantpredictive factor (for response to endocrine therapy) the presence of the receptor in tumor cells is also of prognostic value Eventhough the clinical relevance of the two other sex hormone receptors namely ER120573 and the androgen receptor remains uncleartwo discordant phenomena observed in hormone-dependent breast cancers could be causally related to ER120573-mediated effectsand androgenic actions Nonetheless our understanding of regulatory molecules and resistance mechanisms remains incompletefurther compromising our ability to develop novel therapeutic strategies that could improve disease outcomes This review focuseson the receptor-mediated actions of the sex hormones in breast cancer

1 Introduction

Epidemiological biological and clinical data strongly impli-cate the role of sex hormones primarily estrogens in breastcancer yet their mere presence does not contribute tothe malignant process Inherent in this technically accurateparadox is that while the former supports thewell-establishedlink between estrogens and possibly androgens in thisendocrine-related cancer the latter infers that generation ofthemalignant phenotype requires other cellular componentsPerhaps the most important ldquootherrdquo element is the hormonereceptor While the ligandreceptor construct is conceptuallyvery simple the molecular mechanisms by which sex hor-mones regulate a number of dynamic yet delicate processesin their target tissues are exceedingly more complex

The impetus for undertaking this endeavor was to mergeour increased though by no means complete understandingof the estrogen and androgen receptors in breast cancer Assuch numerous published papers some old but of enduringscientific value were evaluated to support the conclusion

that the nuclear steroid receptors are the essential linkbetweenhormone anddisease And to further enhance readerappreciation of this complex structure the biology of thereceptor is briefly reviewed in order to provide additionalinsight into the proposed mechanisms which promote tumorgrowth as well as facilitate tumor resistance Here the readercan learn a little about the treatment of hormone-dependentbreast cancermore about how cell biologymight improve ourunderstanding of this disease and perhaps better appreciatethe role receptors have in a disease that may be moreappropriately referred to as sex hormone receptor-dependentbreast cancer

2 Evolving Principles

Although an association between estrogens and breast cancerwas recognized over a century ago [1] a valid explanationfor how estrogens exert their tissue-specific actions wasnot forthcoming for another 60 years Rather than theirspeculated role in enzyme-mediated metabolic processes

2 International Journal of Breast Cancer

Table 1 Receptor-mediated effects and features in breast cancer

ER120572 ER120573 ER120572ER120573 heterodimer AR

ProliferationStimulates (in thepresence of E2 and

coactivators)

Suppresses but may dependon variant

(only ER1205731 binds E2 withhigh affinity)

Data support suppressionbut may depend on ER120573variant and density of each

receptor subtype

Stimulates or suppresses(may depend on

concurrent signalingpathways activated)

ApoptosisSuppresses (in thepresence of E2 and

coactivators)

Promotes (but may dependon variant)

Data support promotionbut may depend on ER120573variant and density of each

receptor subtype


concurrent signalingpathways or variant)

PR gene Activates Represses activation Represses activation mdashPrognostic factor Yes Uncertain but possible Uncertain but possible Uncertain but possible

ERE binding Yes Only ER1205731 120573ins and ER1205732bind ERE Yes Androgen response

element (ARE)Dimerization withER120572 and ER1205731 Yes Yes for wild type and 120573ins

ER1205732 binds ER120572 only mdash No

Receptor variants Best characterizedis hER-alpha36

At least 5(ER1205731 (wild type) delta518 aa insert (120573ins) ER120573cx

(ER1205732) and 1205735)

mdash

At least 7 splice variantshave been identified

(AR-V1 AR-V2 AR-V3AR-V4 AR-V5 AR-V6 andAR-V7) but many more

likely to existAF-2 Independent Dependent mdash mdashInteraction withother signalingpathways

Yes Yes Yes Yes

a protein receptor was identified as the critical component tomediate the broad repertoire of hormonal actions includingestrogen-stimulated growth of breast cancer cells [2] Whatlater became the target for new strategies to treat breastcancer the estrogen receptor (ER) was also on the vergeof being associated with the disease in two defining waysFirst as a predictive factor in that the ER emerged as thesingle most useful determinant to guide application of (andlikely response to) endocrine therapies [3] and second asa prognostic factor in that independent of treatment tumorcell expression of this hormone receptor was associated withimproved disease outcomes [4] More recently the ER hasbeen linked to two molecular subtypes of breast canceridentified as luminal A and luminal B [5] Further testingof ER-positive (ER+) tumors by analyzing expression ofa panel of genes resulted in groundbreaking informationfor managing women with early-stage hormone-dependentbreast cancer [6] Translated to a ldquorecurrence scorerdquo themultigene test had like ER both prognostic value (quantifiedthe risk of disease recurrence) and predictive value (estimatedthe benefit of adding chemotherapy)

These noteworthy attributes may have in large part pre-empted the potential importance of the second ER whichwas discovered less than two decades ago [7] Because of thisnew finding what was traditionally referred to as ER subse-quently became known as ER120572 Even though accumulatingdata suggest the more recently identified estrogen receptor(ie ER120573) may have biological and clinical relevance themajority of the published reports support the preeminenceof ER120572 even in tumor cells that coexpress both ER subtypes

While this conclusion is consistent with reports that breastcancer survival was not influenced by ER120573 expression inpatients with ER120572+ or ER120572-negative (ERminus) tumors [8 9]other investigators found a direct correlation between ER120573-positivity and overall survival [10] A confounding factor thatcould provide a partial explanation for this discrepancy is thevariable expression of one or more ER120573 variants in breastcancer (Table 1) Because of the potential clinical relevance ofER120573 a comprehensive discussion of this issue is provided inthe ER120573 section which follows later

Interestingly expression of the androgen receptor (AR)in primary breast tumors and metastatic lesions predatedthe discovery of ER120573 [11] However like ER120573 the clinicalsignificance of its presence in tumor cells remains uncertainNevertheless a number of studies suggest that the AR mayhave prognostic value independent of ER120572 expression Forexample even though AR is frequently present in ER120572+breast cancers AR has also been found in a significantpercentage of ER120572minus tumors [12 13] These observations maybe clinically relevant for the following reason Because tumorcell expression of ER120572 correlates with tumor size histologicgrade and axillary node metastasis it may be difficult toargue that the relatively good prognosis of ER120572+ breastcancers should be attributed in part to coexpressed ARHowever the finding that expression of AR in ER120572minus tumorswas associated with increased age postmenopausal statuslower tumor grade smaller tumor size and significantlyimproved disease-free survival suggests otherwise [13]More-over the absence of AR appeared to be associated with higherlevels of Ki-67 a cell proliferation marker Collectively these

International Journal of Breast Cancer 3

(AB)

Gene

mRNA

Protein (domain)

ER120572 Domains (homology)

ER1205731(wt)

Exons 1 2 3 4 5 6 7 8 9

(D) (E) (F)(C)

NH2 terminal (24)

DNA binding (96)

Hinge Hormone binding (58)

COOH terminal

AF-1

AF-1

AF-2

AF-2

3998400

(a)

Gene

Exons 1 2 3 4 5 6 7 8

mRNA

Protein (domain)

AR

(A) (D)(C)(B)

NTD DBD Hinge LBD

AF-1 AF-2

3998400

minusCOOHNHminus

2

(b)

Figure 1 (a) Characterization of the estrogen receptor gene and protein ER120572 and ER120573 are encoded by two distinct genes the ER120572 gene islocalized to chromosome 6q24ndash27 the ER120573 gene is located on chromosome 14q21-22The gene transcripts are composed of 9 exonsThe twoencoded proteins differ in number of amino acids with ER120572 being slightly longer 595 versus 530 Both proteins have five distinct domainsthree of which have relative degrees of homology The domain with the greatest disparity resides in the AB domain which may accountfor many of the antagonistic actions observed between the two ERs (b) Characterization of the androgen receptor gene and protein Thehuman androgen receptor gene is situated on the long arm of the X-chromosome q11-12 The organization of the protein coding region issimilar to that of the estrogen receptor but is divided over 8 exons The sequence encoding the N-terminal domain (NTD) is found in exon 1Similar to the ER the functionality of the DNA-binding domain (DBD) is provided by a motif comprised of two zinc fingers (UU) encodedby exons 2 and 3 The first zinc finger mediates DNA recognition while the second mediates DNA-dependent dimerization Message for theligand-binding domain (LBD) is distributed over the remaining five exons

data highlight the possibility that sole expression of AR intumor cells may not only be a prognostic indicator but alsoa therapeutic target [14]

What may be most important are the actions medi-ated through each receptor (or the confluence of receptor-mediated actions) on tumor cells and ultimately on diseaseoutcomes Hence a better understanding of the biology ofthese receptors may provide part of the answer

3 Receptor Biology

The sex hormone receptors which belong to thesteroidthyroid superfamily of nuclear receptors mediatethe genomic action of estrogens by acting as ligand-dependent transcription factors [15] All members of thehormone-inducible nuclear receptors share three distinctbut not autonomously functioning domains (Figure 1)First although the NH

2-terminal domain (NTD) contains

activating factor (AF)-1 which serves as the foci fortranscription factor interaction and target-gene activationthe activities of the AF-1 domain differ substantially betweenthe two ERs [16] The nature of this disparity is discussed inthe ER120572ER120573 heterodimer section Next the DNA-bindingdomain (DBD) contains two highly conserved zinc-fingerregions that are essential for high-affinity binding to estrogenresponse elements (EREs) in target genes and comodulatingreceptor dimerization with the ligand-binding domain(LBD) And third the C-terminus domain mediates ligand-binding receptor dimerization and nuclear translocationLocalized to the latter domain is AF-2

Although having similar functional domains a criticalcomponent of signaling mediated through AR depends onreceptor dimerization of which three forms have beendescribed There is convincing evidence that dimerizationmediated through the DBD is perhaps the most important

[17 18] Of note the DBD of both AR and ER is enriched withtwo cysteine zinc finger motifs and a C-terminal extension(CTE) [19] However in contrast to the ERs the first 12amino acids of the CTE are essential for AR-specific DNAbinding [20 21] A second form of AR dimerization occursthrough an interaction between two discrete sites in the N-terminal and C-terminal (NC) [22] Induced only by ARagonists such as 5120572-dihydrotestosterone and testosterone theNC interaction stabilizes the receptor by slowing the rateof steroid dissociation and receptor degradation [23 24]Furthermore the NC interaction appears to be a criticalregulator of chromatin binding and transcription [25] Lastlycompared to LBD-mediated dimerization (the third form)of ER much less is known about the specific sites involvedwith AR [26] Collectively our current knowledge stronglysuggests that dimerization processed through the DBD is anabsolute requirement for AR-mediated signaling

Even though our understanding of the receptor multi-plex continues to evolve construction of exquisite three-dimensional models has made it possible to better appre-ciate and even visualize the submicroscopic precision ofthe hormonereceptor interaction The primal event of lig-and binding at the C-terminal end induces conformationalchanges in the receptor and activates intrinsic AF-2 Crys-tallographic studies of the LBD revealed that the AF-2interaction platform is composed of five helices the mostimportant of which appears to be positioning of helix 12When estradiol binds ER120572 helix 12 is oriented over theligand-binding pocket creating an ldquoagonistrdquo interface forrecruitment of coactivators (Figure 2) [27] On the otherhand the tamoxifenER120572 complex results in displacementof helix 12 from its agonist position and instead occupiesthe lipophilic pocket formed by helices 3 56 and 11 Inthis context helix 12 disrupts the coactivator interactivesurface Hence ligand-induced reorientation of helix 12 is not


H10

H6 H5

H9

H12

H11

H3

(a) Unliganded LBD (b) Estrogen-LBD complex (c) SERM-LBD complex

N terminus

C terminus

N terminus

H11H6

H3

N terminus

H3

H11C terminus

H6

H5 H5H2

H1

H4

H8

H7

HHHSERM

E2

(AB) (C) (D) (E) (F)

ER120572 AF1 AF2

Figure 2 Monomeric modeling of ER120572 LBDThe LBD (a) is a three-dimensional configuration composed of three folded strata The centralcore is comprised of helices 5 6 9 and 10 which is positioned between two layers one composed of helices 1ndash4 the other helices 7 8 and11 The size of the binding cavity is approximately two-fold greater than the molecular volume of estradiol E2 binds diagonally (b) betweenhelices 11 6 and 3 and induces a conformational change in the LBD Devoid of contact with the ligand helix 12 (in red) is repositioned thusproviding a protective seal over the binding cavity Reorientation of helix 12 in this manner intrinsically generates AF2 recruits coactivatorsand promotes transcription However when the receptor binds selective estrogen receptor modulator or SERM (c) the length of the SERMsside chain exceeds the confines of the binding cavity As a result helix 12 is misaligned over the binding pocket Diffraction studies indicatehelix 12 is rotated 130∘ toward the N terminus of the LBD

only an important feature which discriminates ER agonistsfrom antagonists but also essential for receptor-mediatedtranscriptional activity Similarly androgen-bound receptorpromotes conformational rearrangements in the LBD result-ing in formation of AF-2 [28] Interesting however unlikeER AF-2 which is the principal mediator of transcriptionalactivity through coregulator binding in the LBD the ARAF-2 domain preferentially interacts with amino acid motifsfound in the N-terminal domain As such recruited andbound coregulators make the NTD of AR the primary site oftranscriptional activity [29 30]

In contrast the molecular basis of how the hormone-bound receptor interacts with the nuclear transcriptionalelements makes the ligand binding process look relativelysimple as recruitment of additional coregulators and involve-ment of epigenetic proteins has been shown to be essentialin order to fine tune hormonal activity [31] In additiontranscription can be activated or repressed depending on therecruitment or balance of the comodulatory componentsExamples of both types of transcriptional activity are illus-trated using estrogen actions on the skeleton as osteocytescontain ER120572 (Figure 3)Whereasmany of the genes that affectbone metabolism have been identified the manner in whichtranscription takes place depends on surreptitiously preciseinteractions with a number of coactivator complexes

Although negative feedback is a unique biological charac-teristic of the endocrine system molecular evidence suggeststhat part of the mechanism for self-attenuation or inhibitionof receptor-mediated signaling depends on the presence ofcorepressors (Figure 3) As indicated previously estrogen-induced rotation of helix 12within theAF-2 domain facilitates

coactivator binding However in the presence of the anti-estrogens tamoxifen and raloxifine an alternative conforma-tion in the LBD of ER in which helix 12 blocks the coactivatorrecognition site results which favors corepressor binding [27]

In essence the ultimate effect of hormones on target tissuedepends on the balance of coactivators and corepressorsrecruited to the receptor This concept is relevant in breastcancer because receptor-mediated effects appear to resultfrom both upregulation of specific genes that contribute totumor growth and survival as well as downregulation of genesthat possess repressive effects on proliferation and apoptosisIndeed ER120572-targeted gene expression can be downregulatedin the presence of receptor corepressors which consequentlyblunt the effect of estrogens on tumor cell proliferation[32] While the impact of corepressors may be restrictedto receptor-expressing (ie ER120572+) and hormone-dependenttumor cells the development of hormone-independent breastcancers could also be partly linked to diminished corepressoractivity This conclusion is supported by the following (1) ithas been shown that corepressors bound to un-liganded ER120572are dislodged by estradiol [33] and (2) these same corepressorcomplexes which are recruited by antiestrogens could con-ceivably contribute to some of tamoxifenrsquos antitumor effect[34]

Summation of these data indicates that activation orrepression of ER120572-mediated DNA transcription depends onmultiple factors all of which appear to be contingent onthe type of ligandreceptor complex formed as well as thebalance between types of comodulatory proteins recruitedIn essence an intrinsic cellular program mediated throughthe hormone receptors follows a blueprint for the repetitive


CirculationE2

Target cell

SWISNF-ACoactivator

Ligand-bound agonist ER form

SERM

SERM-bound antagonist ER form

NCoR Corepressor

ERE ERE

Transcription

mRNA

No transcription

Transcriptional co-activator complex

Nucleus

SRC-1

p300CBP

CARM1

SMRT

A B

Osteocalcin

ER120572

Figure 3 Schematic representation of the genomic effect of estradiol Nuclear translocation of ligand-bound receptor (A) Activationof targeted genes in osteoblasts necessitates recruitment of two chromatin remodeling complexes known as SWISNF-A (switchingdefectivesucrose nonfermenting) as well as coactivators of the p160 family including SRC-1 SRC-2 and SRC-3 (steroid receptor coactivators1 2 and 3) All of the SRCs possess three nuclear receptor (NR) boxes located in the receptor interacting domain which enables directinteraction with ER120572 and two activation domains AD1 and AD2 which serve as binding sites for p300CBP (cointegrator-associatedprotein) and CARM1 (coactivator-associated arginine methyltransferase 1) The importance of these coregulators especially p300CBPrelates to the latterrsquos interaction with the AF-2 domain of the ERs which prompts recruitment of histone acetylases to the receptor Togetherwith the SRC complexes the epigenetic enzyme disrupts DNA stability thus allowing transcription of the target genes (B) Repressionof transcription occurs in a manner opposite to that of activation Upon SERM binding the receptor undergoes conformational changesthat enhance interactions with corepressors Three of the most well-known repressors of ER120572-mediated transcriptional activity are NCoR(nuclear corepressor) silencing mediator of retinoid and thyroid receptor (SMRT) and repressor of ER120572 activity (REA)This transcriptionalcomodulatory apparatus results in inhibition of transcription

remodeling of chromatin regulates the process of gene tran-scription and determines specific endocrine effects on targettissue The importance of the above information is discussedfurther in sections related to the individual receptors

4 Sex Hormone Receptors

41 ER120572 Not by default related to its early discovery butrather by de facto evidence both laboratory and clinical datasupport the conclusion that estrogenic actions in normalbreast as well as in breast cancer are mediated primarilythrough ER120572 Interestingly the effect on mammary gland

development may be direct or indirect Compelling evidenceof a direct effect comes from the finding that comparedto normal mice ER120572-knockout (120572ERKO) mice retain onlyrudimentary mammary ductal structures despite elevatedlevels of circulating estradiol [35] The importance of thereceptor being established led to the intriguing questionwhether oncogene-induced mammary tumors would stilldevelop in 120572ERKO mice Even though tumor-inducingamplified Human EGFR-Related (HER) 2 could still promotemammary carcinogenesis in this estrogen-insensitive milieudevoid of ER120572 onset of tumor appearance was significantlydelayed [36] These data imply that while the presence ofER120572 was not absolutely essential for tumor development


absence of signaling through the hormone receptor tran-siently repressed tumor promotion or progression Estrogensmay also have an indirect effect on breast tissue by upregu-lating a number of growth factor genes including epidermalgrowth factor and insulin-like growth factor-1 both of whichmay influence or have a contributory role in the disease[37 38]

Adding to or possibly superseding the importance oftissue ER120572 expression are the target genes regulated by thereceptor Activated ER120572 induces transcription of a vast arrayof genes which provide valuable insight into the broad rangeof tumor cell responses that can be mediated through thereceptor Depending on the type or balance of comodulatorsrecruited to the LBD the mitogenic effects of estrogens areattributable not only to regulating tumor cell proliferation butalso suppressing tumor cell apoptosis Laboratory evidenceindicates that ER120572 affects transcription of proproliferativegenes such as proliferating cell nuclear antigen (PCNA)and antiapoptotic genes including survivin and Bcl (B-cellleukemia)-2 [39] One of the more intriguing estrogen-responsive genes isWNT11 (a portmanteau of Wg (wingless)in Drosophila and INT 1 (the mammalian homologue ofWg)) [40] Although there is a strong association betweenWnt11 gene expression and hormone-independent growth ofprostate cancer cells its role in breast cancer may not bethrough Wnt11-mediated tumor cell proliferation but ratherinhibition of apoptosis

It is important to emphasize that the list of ER120572 targetgenes mentioned above is by no means exhaustive as othertypes of genes and their individual role in signal transductiontranscription coactivation and metabolic enzyme processesare also likely to be relevant but were not included Inaddition the genomic actions of estrogen can be furthercomplicated when ER120573 is coexpressed in the same cell

42 ER120573 Regardless whether the terms endocrine respon-sive hormone dependent or ER positive are used to classifya specific subtype of breast cancer all three descriptorsrefer singularly to ER120572 Notwithstanding ER120572rsquos distinctivestatus data continue to accumulate regarding the potentialrelevance of the second estrogen receptor Perhaps the mostsignificant biological difference between the two receptors isthe growth suppressive effects ER120573 imparts on breast cancercells [41ndash44] An ingenious in vitro study conducted usingER120573-transfected MCF-7 (ER120572-positive) cells demonstratedthe impact on estrogen-mediated cellular responses whenboth receptors are expressed In order to establish expressionof the approximate percentage of ER120573 to ER120572 (ie 30)observed in most breast cancers cells were infected withdifferent numbers of ER120573 adenovirus [41] By doing this theinvestigators were also able to assess the effect different levelsof ER120573 expression had on endogenous ER120572 protein levelsNotably ER120572 protein levels decreased significantly in cellswhere ER120573 expression exceeded that ER120572 while expressionof ER120572 was unchanged in cells that had the appropriate ratioof receptors

Interestingly ER120573-induced suppression of tumor cellproliferation has been observed to occur with or without

estrogen [42] Compared to control tumor cells inducedexpression of ER120573 in MCF-7 cells cultured with estradiolresulted in a dramatic reduction in cell growth Of notealso a reduction in the basal growth rate was observed inER120573 expressing MCF-7 cells (compared to control tumorcells) in media devoid of ligand Transcript analysis of thecells provided some plausiblemechanisms for the suppressiveeffects of ER120573 Several proteins involved in cell cycle pro-gressioncell proliferation including CDC25A (cell divisioncycle 25 homolog A) the E2F1 transcription factor and theantiapoptotic protein survivin were all downregulated byER120573 In addition p21WAF1 a negative regulator of the cellcycle was upregulated by ER120573 Collectively these findingsindicated that the observed effect on MCF-7 cells occurredby modulating both positive and negative regulators of cellgrowth

In addition to affecting tumor cell proliferation andsurvival lower expression of ER120573 in breast cancer (comparedto normal breast) suggests the receptor may also have arole in the tumorigenic process Engineered receptor-nullMDA-MB-231 breast cancer cells were transfected with eitherER120572 or ER120573 [43] In the presence of estrogen both proteinsunderwent nuclear translocation and were transcriptionallyactive However contrary to their (similar) effect on severalestrogen-targeted genes only ER120572 could induce the proto-oncogene c-myc Hence in contrast to the proliferative effectof ER120572 ER120573-mediated transcriptional activation appears tobe protective against hormone-dependent breast cancers

Although coexpression of both ER120572 and ER120573 has beencommonly observed two studies found that approximatelyhalf of all ER120572minus breast tumors expressed ER120573 [8 45]Of interest also the absence of ER120572 which characterizestwo other molecular breast cancer phenotypes (ie HER2and basal-like) somewhat surprisingly expressed ER120573 in asubstantial number of tumor specimens [8] Even thoughthe full implications are not known an inverse relationshipbetween prognostic features such as tumor grade tumorsize and node involvement and ER120573 expression has beenreported [8] In addition the presence of ER120573 has beenfound to correlate with improvements in a number of diseaseendpoints including relapse-free survival and overall survival[9 10] however conflicting data have also been reported[46 47] Because of the potential value of measuring ER120573 itis important to reconcile these disparate clinical observationsEven though numerous publications suggest that the actionsof ER120573 are markedly different from ER120572 with the formerfunctioning as a tumor suppressor one major confoundingfactor that could partially explain the discordant findingsmay be related to ER120573 variants of which (other than wildtype) at least four have been identified (Figure 4) Becausemany studies analyzed ER120573 at the transcript level usingprimer sequences common to all variants identification ofwhat may be functionally distinct isoforms of the receptorwas not ascertained [48 49] For example while estrogenbinds to ER1205731 (wild type) [50] and induces transcription ofanti-proliferative and pro-apoptotic genes none of the otherfour variants exhibit high ligand binding affinity Hence theapparent protective effect of ER1205731 against ER120572-dependent


AF-1 DBD LBDAF-2 F

bp 812-950 deleted

ER120572

ER1205731 (wt)

ER1205732

ER1205735

ER1205731205755

ER120573ins

Splice-variants

H

Insertion of 18 aa in LBD (aa 320ndash337)

Nminus

Nminus

Nminus

Nminus

Nminus

Nminus

minusC

minusC

minusC

minusC

minusC

minusC

Figure 4 ER120573 splice variants The AF1 and AF2 domains exhibit the least homology between ER1205731 and ER120572 ER1205732 is nearly identical toER1205731 except that the last 61 amino acids (aa) are replaced by 26 novel aa (indicated by the green portion of the receptor) As such the 1205732splice variant is comprised of 495 aa Similarly the last 65 aa of ER1205735 has been replaced by 7 other aa resulting in a 472 aa protein Of notetruncation of the LBDAF1 domains of 1205732 and 1205735 results in loss of ligand-binding activity while conservation of their DBD maintains thelikelihood of ERE binding Estrogen binding to the delta5 splice variant is compromised by deletion of nucleotides 812ndash950 (139 base pairs(bp)) in the LBD The result of the 18 aa insertion into what is essentially ER1205732 markedly diminishes ligand binding

breast tumorsmay not extend to hormone-dependent tumorsthat coexpress express ER1205732 or ER1205735 [42 51] Transcriptionalactivity also depends on the each variantrsquos ability to bindEREs much uncertainty exists in this regard with ER1205735and ER1205755 [52 53] Other peculiarities that could add to theinconsistent findings include the relatively small numbers ofpatients studied and immunohistochemical detection of onlyER1205731 in tumor samples the primary reason for the latter isoften attributed to lack of variant-specific antibodies [54]Finally what may be extremely important is the dominantnegative activity of ER1205731 ER1205732 and ER120573ins against ER120572which is discussed in the following section

43 ER120572ER1205731 Heterodimer Even though the ERs areencoded by two different genes [55] the receptors sharea number of similarities For example the homology ofthe DNA (C) binding domain is nearly identical theirtransactivation properties are similar and both receptorsbind to consensus ERE Nonetheless and despite someoverlapping gene regulatory activities substantial structuraland functional differences between the two transcription

factors have been reported [16] Of the five major domainsthe greatest between-receptor disparities occur in the N-terminus (AB domain) and ligand-binding (E) domainsTherelevance of these findings relates to transcriptional AF-1and AF-2 which are localized to the AB and E domainsrespectively Furthermore AF-1 and AF-2 determine bothcell- and promoter-specific activities as well as interactionswith comodulatory proteins [16] In addition each receptorrsquosdependence on AF-2 is remarkably different Whereas AF-1of ER120572 can function independently of ligand and AF-2 thatof ER1205731 appears totally dependent on ligand-activated AF-2 Moreover when AF-1 and AF-2 are both activated thefunctional activity of homodimeric ER120572 predominates overthe ER1205731 homodimer [16]

However another aspect of the dimer concept completelydebunks the notion of ER120573rsquos subservient role in relationto ER120572-mediated transcriptional activity Whereas genomicactions of estrogens resulting in tumor cell proliferation andsurvival have been shown to occur via homodimeric ER120572there is the distinct possibility that some of the ER120573 variantscould antagonize these effects through heterodimerization


[56ndash59] Indeed ER120572ER1205731 heterodimers have been localizedto specific DNA binding regions of a number of genesimplicated in cell proliferation [60] Notable also not onlyare some ER120572-inducible genes downregulated by the 1205721205731heterodimer but also increased transcription of genes notaffected by either homodimer [61 62] However one ofthe more confounding issues related to ER120573 involves theformation of ER120572ER120573-splice variant heterodimers Becausetamoxifen has pure antagonist effects on ER1205731 the findingthat a greater proportion of ER1205732-negative tumors respondedto the antiestrogen implies that expression of ER1205732 isassociated with poor response and hence clinical outcomesThis notion is certainly consistent with the concept thatantitumor effects achieved through ER120572 blockade could bepartially counteracted by inhibiting the growth inhibitoryeffects mediated by ER1205732 [49] On the other hand somestudies have found that expression of ER1205732 was associatedwith significant improvement in relapse-free survival andoverall survival [63 64]Though the findings are inconsistentthe clinical endpoints may be independent of tamoxifenrsquoseffect on ER1205732 (as well as formation of the 1205721205731 heterodimer)because of altered ligand binding due to changes in thetruncated C-terminus of the protein and loss of the AF-2domain [65]

Of interest also is the expression of the progesteronereceptor (PR) which is known to be regulated by ER120572 [66]Because the presence of ER1205731 has been shown to represstransactivation of the PR gene [67] the heterodimer ina manner similar to its antiproliferative effects could alsosuppress this ER120572-target gene Moreover this finding couldexplain the clinical phenomenon of ER+PRminus breast cancersThese findings suggest not only that genomic action (andhence biological effect) of estrogens differs depending onreceptor dimeric state but also the possibility of a reciprocalinfluence each receptor has on the other (Table 1)

44 AR The finding that expression of AR is ubiquitous inboth males and females suggests that androgens are likelyto have an impact in various tissues including the breastEven though the actions of androgens are believed to opposethat of estrogens the inhibitory effect of androgens on breasttissue depends largely on the relative tissue concentrations ofboth types of hormones as well as their receptor-mediatedactions This conclusion is consistent with two observations(1) breasts do not undergo normal development in girlsdiagnosed with androgen-secreting adrenal tumors despiteadequate circulating estrogens [68] and (2) development ofgynecomastia in men treated with AR blockers for prostatecancer [69] Clinically a possible link has been establishedbetween AR expression and outcomes in certain subsets ofbreast cancer [70 71] Moreover therapeutic application ofandrogens predated the selective estrogen receptor modula-tors in postmenopausal women with breast cancer [72 73]

Relative to ER120572 the role of androgens in breast cancergrowth and disease progression is less well understoodThis level of uncertainty and perhaps appreciation persistsin spite of the apparent correlation between tumor cellexpression of AR in the majority of human breast cancers

and various features of the disease mentioned earlier inthis paper The importance attached to this discordancenecessitates a brief discussion of several salient issues Firstepidemiological studies have on occasion reached differentconclusions with respect to androgens and breast cancerwith the hormones either enhancing the protection againstor increasing the risk for the disease [74] One of themajor reasons for this discrepancy relates to the validity ofthe correlation between disease risk and serum androgenconcentrations [75] Reliance on blood levels alone howeverobscures the potential importance of extragonadal synthesisof androgens (and estrogens) Identification of all the req-uisite enzymes including the 5120572-reductases and both 3120573-and 17120573-hydroxysteroid dehydrogenases in peripheral tissuesupports the relevance of a biological process known asintracrinology (Figure 5) That locally produced androgenscan exert their actions in an intracrine manner may haveadded importance especially in postmenopausal womenwho not only have a higher risk of breast cancer but whoalso rely on peripheral synthesis of nearly all sex hormonesfrom adrenal-derived dehydroepiandrosterone (DHEA) [76]Moreover the best indicator of the total androgen reservoiras well as androgenic activity has been shown to be theconjugated metabolites of dihydrotestosterone (DHT) notthe active hormone [76]

Second results of in vitro studies are discordant even inAR+ breast cancer cell lines [77] When exposed to DHT aproliferative response occurred in both MDA-MB-453 cells(AR+ERminus) and MCF-7 (AR+ER+) cell lines however ananti-proliferative effect was observed in two other AR+ER+cell lines T47-D and ZR-75l One of the more intriguingexplanations for the differential effect on proliferation inERminus and ER+ tumor cell lines may involve an interactionbetween AR and HER2 as both receptors are coexpressedin approximately 50 of ERminus breast cancers [78] In breastcancers classified as molecular apocrine subtype androgen-induced proliferation involves activation of the extracellularsignal-regulated-kinase-(ERK-) signal transduction pathwayHowever the AR link to ERK has been shown to bedependent on transcriptional upregulation of theHER2 geneHence a functional feedback loop has been postulated in thistype of breast cancer which includes AR HER2 ERK and anERK transcription factor that binds to a promoter region ontheAR gene [79] What is also notable about this study is thata number of possible confounding causes for the divergentcellular responses such as cell density at time of drug exposureand serum used in the culture medium were eliminatedby the meticulous methodology used by the investigatorsAnother plausible explanation for the discrepant resultsis the involvement of AR-independent pathways Becauseandrogens such as DHT can bemetabolized (not aromatized)in vitro onemetabolite has been shown to bind ER120572 resultingin the proliferation of the MCF-7 cells [80] It should alsobe mentioned that even though AR levels varied markedlybetween the different cell lines receptor numbers alonecannot account for the divergent effects on proliferationThisconclusion is supported by the contrasting results observedin the two cell lines with the highest level of AR MDA-MB-453 and ZR-75l In addition despite a 6-fold lower AR


Adipose tissue

Adrenalgland

DHEA

4-dione

A-dione

Androsterone

Estrone

Aromatase

DHEA-S

Estradiol

Testosterone

Dihydrotestosterone

Aromatase

3120573-HSD

5120572-red

3120572-HSD

17120573-HSD1 7 12

5120572-red

Figure 5 Sex steroidogenesis via the intracrine pathway Androgens and estrogens synthesized in peripheral tissue including thebreast require the presence of DHEA an inactive precursor derived from the adrenal gland and all of the appropriate enzymes Inaddition to their synthesis sex steroids are also inactivated in the same tissue thus minimizing widespread systemic effects DHEA =dehydroepiandrosterone DHEA-S = DHEA sulfated 4-dione = androstenedione A-dione = 5120572-androstenedione 3120572- 3120573- and 17120573HSD =hydroxysteroid dehydrogenase 5120572-red = reductase

expression MCF-7 cells had a similar proliferative responseas MDA-MB-453 cells

Even more perplexing is one other finding related toandrogen action in MCF-7 breast cancer cells While prolif-eration ofMCF-7 breast cancer cells has been shown to occureven in the absence of estrogens the proliferative effect maynot be mediated through the androgen receptor pathway Inthe presence of supra-physiological concentrations of DHTnuclear translocation of both AR and ER occurred That thestimulatory effect of DHT could have been mediated via ERwas supported by increased expression of PR and the inabilityof antiandrogens to inhibit tumor cell growth [81] This invitro approach demonstrated that at physiological levels ofDHT the androgen does not compete with estradiol for ER120572binding In addition an intriguing in vivo correlate exists onewhere breast tumor cells with negligible expression of ER120572 areexposed to high levels of androgens In this clinically possiblesetting it is rational to suggest that the rather promiscuousaffinity of androgen or an androgen metabolite [82] for theestrogen receptor provides a plausible explanation for tumorsbeing characterized as ERminusPR+

Third clinical data indicate that expression of ARoccurs more frequently than ER in breast tumor tissueInterestingly 10ndash35 of triple negative and up to 60of ERminusPRminusHER2+ breast cancers have been reported toexpress AR [71 83ndash85] However unlike ER120572 AR expression

alonemay not be predictive of response as anticancer benefitshave been demonstrated with both androgens and anti-androgens These confounding findings strongly suggest thatother factors including signaling through the epidermalgrowth factor receptor (EGFR) and HER2 pathways oractivation of a key intermediary downstream kinase such asmitogen-activated protein kinase (MAPK) may contributeto the complex repertoire of androgen-mediated effects [8687] The contribution of other signaling pathways has beennicely demonstrated in an ER120572minusPRminus breast cancer cellline engineered to express AR While upregulation of theAR-target gene p21WAF1 promoted tumor cell proliferationthrough the MAPK pathway hyperactivation of MAPK byconcurrent AR and EGFR-signaling pathways caused tumorgrowth suppression [88 89]

Fourth despite the frequency of AR expression in pri-mary breast cancers the function and role of the receptormay not be the same as in prostate cancer This conclusion issupported by several findings regarding androgen signalingin both endocrine-related cancers For instance AR geneamplification is frequently observed in prostate cancer butnot in breast cancer despite receptor overexpression [90]Whereas high AR expression has been correlated with pooreroutcomes in prostate cancer some investigators have founda direct correlation between AR expression and survival inpatients with breast cancer [13 91 92] Nonetheless high


AR expression may provide an advantage for both cancersespecially since serum androgen and adrenal-derived DHEAlevels althoughmarkedly reduced by androgen-ablative ther-apy or aging can be partially blunted by the process ofintracrinology

5 Hormone Receptor Milieu in Breast Cancer

Very compelling evidence support the belief that in contrastto estrogen-induced proliferation of ER120572+ tumor cells tumorsuppressive effects are mediated through ER120573 regardless ofthe second receptor that is expressed alone or in the presenceof ER120572 [93] This distinction may be clinically relevantto what has been traditionally labeled hormone receptorpositive and possibly even hormone receptor negative breastcancer One therapeutic implication relates to endoxifenoften regarded as the most potent metabolite of tamoxifen[94] Exposure of MCF-7 (control) and ER1205731-transfectedMCF-7 cells to estrogen and endoxifen resulted in some strik-ing between-cell differences Unlike the rapid proteosomaldegradation of ER120572 in control cells stable accumulation ofER1205731 was observed in the transfected cells Notably the ER120572protein levels were also protected from enzymatic catabolismin the transfected cells a finding supported by immuno-precipitation assays which indicated that the antiestrogenpromoted formation of receptor heterodimers In additionendoxifen inhibited the upregulation of estrogen-responsivegenes such as cyclin D1 and PR in both cell lines Of notealso significantly lower concentrations of the anti-estrogen(ie 40 nM compared to 1000 nM) were required for thesame degree of inhibition in the ER1205731-transfected cells Thisfinding suggested that the presence of ER1205731 appeared tointensify the antagonistic effects of endoxifen Though spec-ulative it is conceivable that the expression status of ER1205731which was not assessed in all of the CYP2D6 studies couldpartially explain the conflicting predictive role of CYP2D6pharmacogenomics and breast cancer outcomes [95] Lastly17 biological pathways were found to be unique to either thecontrol or the MCF-7 ER1205731 cell lines Two ER120572-mediatedpathways one involving the regulation of G1S cell cycleprogression and the other cell migration could be affectedby endoxifen only if the cells coexpressed ER1205731 Even thoughthe gene expression pattern observed in the transfected cellscould be linked to either ER homodimer the degradation ofER120572 suggests that changes in the gene profile as well as theenhanced antiestrogen effect of endoxifen may result fromthe inhibition of ER120572ER1205731 heterodimer

Interesting also is the apparent paradox related to therole of estrogens in tumor cell survival and tumor cell deathwith the latter being mediated by mechanisms other thanhormone deprivation As certain as we were about tumorcell survival both clinical and laboratory data unexpectedlydemonstrated that under certain circumstances introduc-tion of low doses of estrogens appears to have a protectiveeffect on breast cancer [96 97] This ldquoanti-tumorrdquo effectwas observed among surgically castrated postmenopausalwomen randomized to hormone replacement therapy as wellas in a tamoxifen-resistant MCF-7 cell line Notably long-term estrogen deprivation appears to modulate apoptotic

pathways of both normal and cancer cells either by induc-ing expression of proteins involved in the extrinsic cell-death pathway such as FasRFasL or affecting regulatorycomponents of the mitochondrial (ie intrinsic) apoptoticpathway including induction of the proapoptotic proteinsBax Bak and Bim [98] While this may be the most rea-sonable explanation it is also possible that actions mediatedby ER1205731 or AR could have modulated cell survival Whatmay be more intriguing about AR as a breast cancer targetrelates to a novel finding in ERminusAR+HER2+ tumor samples[84] Particularly alluring was the gene expression profileone aspect of which indicated that AR-mediated signalingupregulated WNT7B transcription and activated 120573-cateninThrough their collaborative effort AR and 120573-catenin weredirectly linked to androgen-induced HER3 expression andindirectly to the pernicious tumor characteristics impartedby the HER2HER3 heterodimer [99] As such suppressionof HER2 signaling as well as formation of the heterodimercould be achieved by AR inhibitors

Equally engaging is the concept that aberrations of theencoding genesmay not only influence hormonal actions butalso breast cancer risk That hormone insensitivity observedwith other nuclear receptors has been positively linked toalterations in their respective genes deletions rearrange-ments and point mutations in the ER120572 gene could vis-a-vis also be associated with susceptibility to developing thedisease Indeed even before data from the Human Genomeand the HapMap projects were published genotyping tech-nology was being utilized to determine whether sequencevariations or single-nucleotide polymorphisms (SNPs) in theER genes were associated with disease risk Two of the bettercharacterized variants in the ER120572 gene are PvuII a two-allele(1 and 0) restriction fragment-length polymorphism (RFLP)and Xbal Even so conflicting published data abound Forexample results of several studies indicated a significant butnot complete correlation between the PvuII genotype andER120572-positive breast cancers [100 101] In contrast anotherstudy found that the prevalence of ER120572-positive tumors washighest among women homozygous or heterozygous for the0 (ie Pvu00 and Pvu01) allele and lowest in those harboringthe ER120572 gene PvuII alleles [102] Despite the contradictorydata the relatively weak overall correlation between RFLPgenotype and ER120572 expression found in both studies suggeststhat this aberration in genomic sequence may not be linkedto disease risk or receptor phenotype The latter conclusionis supported by numerous other studies which found nofrequency difference of the PvuII polymorphism betweenbreast cancer cases and controls [102ndash104] Similar contraryfindings have been reported for the Xbal polymorphism [101103 104] Polymorphisms of the ER1205731 gene have also beendetected and though there may be an association betweenthe identified SNPs and disease risk the data are way toopreliminary to be of substantive value [105ndash107]

6 Conclusion

Embedded in the widely accepted dogma that estrogens arecarcinogenic in breast tissue is the pivotal role of the estrogen


receptor specifically ER120572 Nonetheless accumulating evi-dence suggests that ER1205731 and possibly AR also appear tohave influential actions in the mammary gland If the clinicalrelevance of especially ER1205731 andARcan be firmly establishedseveral new intrinsic subtypes of endocrine-sensitive breastcancers may emerge and subsequently undergo gene expres-sion profiling Unique in terms of their hormone dependencyeach subtype may require a different hormonal approach inorder to improve disease outcome And while reference toER+ (ie ER120572+PRminus) breast cancer will still be appropri-ate designation of specific double (ie ER120572ER120573-variantER120572AR and ER120573-variantAR) or triple (ie ER120572 ER120573-variant and AR) hormone receptor-positive tumors mayhave greater clinical significance Moreover truly hormonereceptor-negative breast cancers are apt to be less frequentlydiagnosed incrementally more likely not to benefit from anytype of hormonal intervention and perhaps even be of betterprognostic value

Although ER120572 is one of the oldest tumor targets clinicalevidence validates the conclusion that estrogen-deprivationstrategies is the most effective way to treat hormone-dependent breast cancer And despite the translationalachievement between laboratory and clinic with approvalof agents targeting ER120572 the expected concordance betweenconstruct inhibition and tumor eradication has in somerespects been overestimated The apparent incongruencesuggests that mere identification of the target(s) regardlessof its (their) purported functional importance exaggeratesour knowledge of tumor cell signaling pathways whichultimately controls cancer cell growth and survival Untilall hormone receptor components are fully understood theoptimal clinical impact of antihormonal therapies will not befully realized

Conflict of Interests

The authors declare that they have no conflict of interests

References

[1] S Boyd ldquoOn oophorectomy in cancer of the breastrdquo BritishMedical Journal vol 2 pp 1161ndash1167 1900

[2] V E Jensen I H Jacobson A A Walf and A C Frye ldquoBasicguides to the mechanism of estrogen actionrdquo Recent Progress inHormone Research vol 18 pp 318ndash414 1962

[3] M P Cole C T Jones and I D Todd ldquoA new anti-oestrogenicagent in late breast cancer an early clinical appraisal ofICI46474rdquo British Journal of Cancer vol 25 no 2 pp 270ndash2751971

[4] B Fisher C Redmond E R Fisher and R Caplan ldquoRelativeworth of estrogen or progesterone receptor and pathologiccharacteristics of differentiation as indicators of prognosis innode negative breast cancer patients findings from nationalsurgical adjuvant breast and bowel project protocol B-06rdquoJournal of Clinical Oncology vol 6 no 7 pp 1076ndash1087 1988

[5] T Soslashrlie C M Perou R Tibshirani et al ldquoGene expressionpatterns of breast carcinomas distinguish tumor subclasses withclinical implicationsrdquo Proceedings of the National Academy ofSciences of theUnited States of America vol 98 no 19 pp 10869ndash10874 2001

[6] S Paik G Tang S Shak et al ldquoGene expression and bene-fit of chemotherapy in women with node-negative estrogenreceptor-positive breast cancerrdquo Journal of Clinical Oncologyvol 24 no 23 pp 3726ndash3734 2006

[7] G G J M Kuiper E Enmark M Pelto-Huikko S Nilssonand J-A Gustafsson ldquoCloning of a novel estrogen receptorexpressed in rat prostate and ovaryrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 93 no12 pp 5925ndash5930 1996

[8] J D Marotti L C Collins R Hu and R M Tamimi ldquoEstrogenreceptor-120573 expression in invasive breast cancer in relation tomolecular phenotype results from the nursesrsquo health studyrdquoModern Pathology vol 23 no 2 pp 197ndash204 2010

[9] W R Miller T J Anderson J M Dixon and P T K SaundersldquoOestrogen receptor120573 andneoadjuvant therapywith tamoxifenprediction of response and effects of treatmentrdquo British Journalof Cancer vol 94 no 9 pp 1333ndash1338 2006

[10] N Honma R Horii T Iwase et al ldquoClinical importance ofestrogen receptor-120573 evaluation in breast cancer patients treatedwith adjuvant tamoxifen therapyrdquo Journal of Clinical Oncologyvol 26 no 22 pp 3727ndash3734 2008

[11] E Engelsman C B Korsten J P Persijn and F J CletonldquoProceedings oestrogen and androgen receptors in humanbreast cancerrdquo British Journal of Cancer vol 30 no 2 article177 1974

[12] S Park J Koo H S Park et al ldquoExpression of androgenreceptors in primary breast cancerrdquoAnnals of Oncology vol 21no 3 pp 488ndash492 2010

[13] S N Agoff P E Swanson H Linden S E Hawes and T JLawton ldquoAndrogen receptor expression in estrogen receptor-negative breast cancer immunohistochemical clinical andprognostic associationsrdquo American Journal of Clinical Pathol-ogy vol 120 no 5 pp 725ndash731 2003

[14] FMoinfarM Okcu O Tsybrovskyy et al ldquoAndrogen receptorsfrequently are expressed in breast carcinomas potential rele-vance to new therapeutic strategiesrdquo Cancer vol 98 no 4 pp703ndash711 2003

[15] D J Mangelsdorf C Thummel M Beato et al ldquoThe nuclearreceptor superfamily the second decaderdquoCell vol 83 no 6 pp835ndash839 1998

[16] S M Cowley and M G Parker ldquoA comparison of tran-scriptional activation by ER120572 and ER120573rdquo Journal of SteroidBiochemistry and Molecular Biology vol 69 no 1ndash6 pp 165ndash175 1999

[17] M Truss and M Beato ldquoSteroid hormone receptors inter-action with deoxyribonucleic acid and transcription factorsrdquoEndocrine Reviews vol 14 no 4 pp 459ndash479 1993

[18] K Dahlman-Wright A Wright J Gustafsson and J Carlstedt-Duke ldquoInteraction of the glucocorticoid receptor DNA-bindingdomain with DNA as a dimer is mediated by a short segment offive amino acidsrdquo Journal of Biological Chemistry vol 266 no5 pp 3107ndash3112 1991

[19] C K Glass ldquoDifferential recognition of target genes by nuclearreceptor monomers dimers and heterodimersrdquo EndocrineReviews vol 15 no 3 pp 391ndash407 1994

[20] J W R Schwabe L Chapman J T Finch and D RhodesldquoThe crystal structure of the estrogen receptor DNA-bindingdomain bound to DNA how receptors discriminate betweentheir response elementsrdquo Cell vol 75 no 3 pp 567ndash578 1993

[21] E Schoenmakers G Verrijdt B Peeters G Verhoeven WRombauts and F Claessens ldquoDifferences in DNA binding char-acteristics of the androgen and glucocorticoid receptors can


determine hormone-specific responsesrdquo Journal of BiologicalChemistry vol 275 no 16 pp 12290ndash12297 2000

[22] E Langley Z-X Zhou and EMWilson ldquoEvidence for an anti-parallel orientation of the ligand-activated human androgenreceptor dimerrdquo Journal of Biological Chemistry vol 270 no 50pp 29983ndash29990 1995

[23] J A Kemppainen E Langley C-I Wong K Bobseine W RKelce and E M Wilson ldquoDistinguishing androgen receptoragonists and antagonists distinct mechanisms of activation bymedroxyprogesterone acetate and dihydrotestosteronerdquoMolec-ular Endocrinology vol 13 no 3 pp 440ndash454 1999

[24] Z-X Zhou M V Lane J A Kemppainen F S French and EM Wilson ldquoSpecificity of ligand-dependent androgen receptorstabilization receptor domain interactions influence liganddissociation and receptor stabilityrdquo Molecular Endocrinologyvol 9 no 2 pp 208ndash218 1995

[25] J Li J Fu C Toumazou H-G Yoon and J Wong ldquoA role ofthe amino-terminal (N) and carboxyl-terminal (C) interactionin binding of androgen receptor to chromatinrdquo MolecularEndocrinology vol 20 no 4 pp 776ndash785 2006

[26] P Doesburg C W Kuil C A Berrevoets et al ldquoFunctional invivo interaction between the amino-terminal transactivationdomain and the ligand binding domain of the androgenreceptorrdquo Biochemistry vol 36 no 5 pp 1052ndash1064 1997

[27] A M Brzozowski A C W Pike Z Dauter et al ldquoMolecularbasis of agonism and antagonism in the oestrogen receptorrdquoNature vol 389 no 6652 pp 753ndash758 1997

[28] J S Sack K F Kish C Wang et al ldquoCrystallographic struc-tures of the ligand-binding domains of the androgen receptorand its T877A mutant complexed with the natural agonistdihydrotestosteronerdquo Proceedings of the National Academy ofSciences of the United States of America vol 98 no 9 pp 4904ndash4909 2001

[29] D M Heery E Kalkhoven S Hoare and M G ParkerldquoA signature motif in transcriptional co-activators mediatesbinding to nuclear receptorsrdquoNature vol 387 no 6634 pp 733ndash736 1997

[30] G Jenster H A G M Van der Korput J Trapman and A OBrinkmann ldquoIdentification of two transcription activation unitsin the N-terminal domain of the human androgen receptorrdquoJournal of Biological Chemistry vol 270 no 13 pp 7341ndash73461995

[31] C L Smith and B W OrsquoMalley ldquoCoregulator function akey to understanding tissue specificity of selective receptormodulatorsrdquo Endocrine Reviews vol 25 no 1 pp 45ndash71 2004

[32] J Lopez-Garcia M Periyasamy S R Thomas et al ldquoZNF366is an estrogen receptor corepressor that acts through CtBP andhistone deacetylasesrdquo Nucleic Acids Research vol 34 pp 6126ndash6136 2006

[33] T Ishizuka and M A Lazar ldquoThe N-CORhistone deacetylase3 complex is required for repression by thyroid hormonereceptorrdquo Molecular and Cellular Biology vol 23 no 15 pp5122ndash5131 2003

[34] PWebb PNguyen and P J Kushner ldquoDifferential SERMeffectson corepressor binding dictate ER120572 activity in vivordquo Journal ofBiological Chemistry vol 278 no 9 pp 6912ndash6920 2003

[35] W P Bocchinfuso and K S Korach ldquoMammary gland develop-ment and tumorigenesis in estrogen receptor knockout micerdquoJournal of Mammary Gland Biology and Neoplasia vol 2 no 4pp 323ndash334 1997

[36] S C Hewitt W P Bocchinfuso J Zhai et al ldquoLack of ductaldevelopment in the absence of functional estrogen receptor

120572 delays mammary tumor formation induced by transgenicexpression of ErbB2neurdquo Cancer Research vol 62 no 10 pp2798ndash2805 2002

[37] G J Todaro T M Rose C E Spooner M Shoyab and G DPlowman ldquoCellular and viral ligands that interact with the egfreceptorrdquo Seminars in Cancer Biology vol 1 no 4 pp 257ndash2631990

[38] D L Kleinberg ldquoEarly mammary development growth hor-mone and IGF-1rdquo Journal of Mammary Gland Biology andNeoplasia vol 2 no 1 pp 49ndash57 1997

[39] Z Lin S Reierstad C-C Huang and S E Bulun ldquoNovelestrogen receptor-120572 binding sites and estradiol target genesidentified by chromatin immunoprecipitation cloning in breastcancerrdquo Cancer Research vol 67 no 10 pp 5017ndash5024 2007

[40] A Klaus and W Birchmeier ldquoWnt signalling and its impact ondevelopment and cancerrdquo Nature Reviews Cancer vol 8 no 5pp 387ndash398 2008

[41] P Roger M E Sahla S Makela J A Gustafsson P BaldetandH Rochefort ldquoDecreased expression of estrogen receptor 120573protein in proliferative preinvasive mammary tumorsrdquo CancerResearch vol 61 no 6 pp 2537ndash2541 2001

[42] E C Chang J Frasor B Komm and B S KatzenellenbogenldquoImpact of estrogen receptor 120573 on gene networks regulated byestrogen receptor 120572 in breast cancer cellsrdquo Endocrinology vol147 no 10 pp 4831ndash4842 2006

[43] G Lazennec D Bresson A Lucas C Chauveau and F VignonldquoER120573 inhibits proliferation and invasion of breast cancer cellsrdquoEndocrinology vol 142 no 9 pp 4120ndash4130 2001

[44] S Paruthiyil H Parmar V Kerekatte G R Cunha G LFirestone and D C Leitmant ldquoEstrogen receptor 120573 inhibitshuman breast cancer cell proliferation and tumor formation bycausing a G2 cell cycle arrestrdquoCancer Research vol 64 no 1 pp423ndash428 2004

[45] G P Skliris E Leygue L Curtis-Snell P H Watson and LC Murphy ldquoExpression of oestrogen receptor-120573 in oestrogenreceptor-120572 negative human breast tumoursrdquo British Journal ofCancer vol 95 no 5 pp 616ndash626 2006

[46] P A OrsquoNeill M P A Davies A M Shaaban et al ldquoWild-typeoestrogen receptor beta (ER1205731) mRNA and protein expressionin tamoxifen-treated post-menopausal breast cancersrdquo BritishJournal of Cancer vol 91 no 9 pp 1694ndash1702 2004

[47] E V Jensen G Cheng C Palmieri et al ldquoEstrogen receptorsand proliferation markers in primary and recurrent breastcancerrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 98 no 26 pp 15197ndash15202 2001

[48] P D Cremoux C Tran-Perennou C Elie et al ldquoQuantitationof estradiol receptors alpha and beta and progesterone receptorsin human breast tumors by real-time reverse transcription-polymerase chain reaction correlation with protein assaysrdquoBiochemical Pharmacology vol 64 no 3 pp 507ndash515 2002

[49] I Bieche B Parfait I Laurendeau I Girault M Vidaudand R Lidereau ldquoQuantification of estrogen receptor 120572 and 120573expression in sporadic breast cancerrdquo Oncogene vol 20 no 56pp 8109ndash8115 2001

[50] S Saji H Sakaguchi S Andersson M Warner and J-AGustafsson ldquoQuantitative analysis of estrogen receptor proteinsin rat mammary glandrdquo Endocrinology vol 142 no 7 pp 3177ndash3186 2001

[51] S Saji Y Omoto C Shimizu et al ldquoExpression of estrogenreceptor (ER) 120573cx protein in ER120572-positive breast cancer spe-cific correlation with progesterone receptorrdquo Cancer Researchvol 62 no 17 pp 4849ndash4853 2002


[52] E A Vladusic A E Hornby F K Guerra-Vladusic and RLupu ldquoExpression of estrogen receptor 120573 messenger RNAvariant in breast cancerrdquoCancer Research vol 58 no 2 pp 210ndash214 1998

[53] C Palmieri G J Cheng S Saji et al ldquoEstrogen receptor beta inbreast cancerrdquo Endocrine-Related Cancer vol 9 no 1 pp 1ndash132002

[54] K Iwao Y Miyoshi C Egawa N Ikeda F Tsukamoto and SNoguchi ldquoQuantitative analysis of estrogen receptor-alpha and-beta messenger RNA expression in breast carcinoma by real-time polymerase chain reactionrdquo Cancer vol 89 pp 1732ndash17382000

[55] E Enmark M Pelto-Huikko K Grandien et al ldquoHuman estro-gen receptor beta-gene structure chromosomal localizationand expression patternrdquo The Journal of Clinical Endocrinologyamp Metabolism vol 82 no 12 pp 4258ndash4265 1997

[56] L A Helguero M H Faulds J-A Gustafsson and L-AHaldosen ldquoEstrogen receptors alfa (ER

120572) and beta (ER

120573) dif-

ferentially regulate proliferation and apoptosis of the normalmurine mammary epithelial cell line HC11rdquo Oncogene vol 24no 44 pp 6605ndash6616 2005

[57] K Pettersson F Delaunay and J-A Gustafsson ldquoEstrogenreceptor 120573 acts as a dominant regulator of estrogen signalingrdquoOncogene vol 19 no 43 pp 4970ndash4978 2000

[58] S Saji M Hirose and M Toi ldquoClinical significance of estrogenreceptor120573 in breast cancerrdquoCancer Chemotherapy and Pharma-cology vol 56 no 7 supplement pp s21ndashs26 2005

[59] S M Cowley S Hoare S Mosselman and M G ParkerldquoEstrogen receptors 120572 and 120573 form heterodimers on DNArdquoJournal of Biological Chemistry vol 272 no 32 pp 19858ndash198621997

[60] K Pettersson K Grandien G G J M Kuiper and J-A Gustafsson ldquoMouse estrogen receptor 120573 forms estrogenresponse element-binding heterodimers with estrogen receptor120572rdquoMolecular Endocrinology vol 11 no 10 pp 1486ndash1496 1997

[61] L C Murphy B Peng A Lewis et al ldquoInducible upregula-tion of oestrogen receptor-1205731 affects oestrogen and tamoxifenresponsiveness in MCF7 human breast cancer cellsrdquo Journal ofMolecular Endocrinology vol 34 no 2 pp 553ndash566 2005

[62] Z Papoutsi C Zhao M Putnik J-A Gustafsson and KDahlman-Wright ldquoBinding of estrogen receptor 120572120573 het-erodimers to chromatin in MCF-7 cellsrdquo Journal of MolecularEndocrinology vol 43 no 2 pp 65ndash72 2009

[63] M P A Davies P A OrsquoNeill H Innes et al ldquoCorrelationof mRNA for oestrogen receptor beta splice variants ER120573 1ER1205732ER120573cx and ER1205735 with outcome in endocrine-treatedbreast cancerrdquo Journal of Molecular Endocrinology vol 33 no3 pp 773ndash782 2004

[64] C Palmieri E W Lam J Mansi et al ldquoThe expression ofERbetacx in human breast cancer and the relationship toendocrine therapy and survivalrdquo Clinical Cancer Research2004vol 10 pp 2421ndash2428

[65] J T Moore D D McKee K Slentz-Kesler et al ldquoCloningand characterization of human estrogen receptor 120573 isoformsrdquoBiochemical and Biophysical Research Communications vol 247no 1 pp 75ndash78 1998

[66] S C Hewitt and K S Korach ldquoProgesterone action andresponses in the 120572ERKO mouserdquo Steroids vol 65 no 10-11 pp551ndash557 2000

[67] J Matthews B Wihlen M Tujague J Wan A Strom andJ-A Gustafsson ldquoEstrogen receptor (ER) 120573 modulates ER120572-mediated transcriptional activation by altering the recruitment

of c-Fos and c-Jun to estrogen-responsive promotersrdquo Molecu-lar Endocrinology vol 20 no 3 pp 534ndash543 2006

[68] G Forsbach A Guitron-Cantu J Vazquez-Lara M Mota-Morales andM LDıaz-Mendoza ldquoVirilizing adrenal adenomaand primary amenorrhea in a girl with adrenal hyperplasiardquoArchives of Gynecology and Obstetrics vol 263 no 3 pp 134ndash136 2000

[69] A Dobs and M J M Darkes ldquoIncidence and management ofgynecomastia in men treated for prostate cancerrdquo Journal ofUrology vol 174 no 5 pp 1737ndash1742 2005

[70] G Buchanan S N Birrell A A Peters et al ldquoDecreasedandrogen receptor levels and receptor function in breast cancercontribute to the failure of response to medroxyprogesteroneacetaterdquo Cancer Research vol 65 no 18 pp 8487ndash8496 2005

[71] A Gucalp and T A Traina ldquoTriple-negative breast cancer roleof the androgen receptorrdquo Cancer Journal vol 16 no 1 pp 62ndash65 2010

[72] E F Adair and B J Herrmann ldquoThe use of testosteronepropionate in the treatment of advanced carcinoma of thebreastrdquo Annals of Surgery vol 123 pp 1023ndash1035 1946

[73] B J Kennedy ldquoFluoxymesterone therapy in advanced breastcancerrdquo The New England Journal of Medicine vol 259 no 14pp 673ndash675 1958

[74] AH Eliassen S AMissmer S S Tworoger et al ldquoEndogenoussteroid hormone concentrations and risk of breast canceramong premenopausal womenrdquo Journal of the National CancerInstitute vol 98 no 19 pp 1406ndash1415 2006

[75] T J Key P Appleby I Barnes and G Reeves ldquoEndogenoussex hormones and breast cancer in postmenopausal womenreanalysis of nine prospective studiesrdquo Journal of the NationalCancer Institute vol 94 no 8 pp 606ndash616 2002

[76] F Labrie A Belanger L Cusan and B Candas ldquoPhysiolog-ical changes in dehydroepiandrosterone are not reflected byserum levels of active androgens and estrogens but of theirmetabolites intracrinologyrdquo Journal of Clinical Endocrinologyand Metabolism vol 82 no 8 pp 2403ndash2409 1997

[77] S N Birrell J M Bentel T E Hickey et al ldquoAndrogens inducedivergent proliferative responses in human breast cancer celllinesrdquo Journal of Steroid Biochemistry and Molecular Biologyvol 52 no 5 pp 459ndash467 1995

[78] A Naderi and L Hughes-Davies ldquoA functionally significantcross-talk between androgen receptor and ErbB2 pathways inestrogen receptor negative breast cancerrdquo Neoplasia vol 10 no6 pp 542ndash548 2008

[79] K M Chia J Liu G D Francis and A Naderi ldquoA feedbackloop between androgen receptor and erk signaling in estrogenreceptor-negative breast cancerrdquo Neoplasia vol 13 no 2 pp154ndash166 2011

[80] R Roy S Dauvois F Labrie and A Belanger ldquoEstrogen-stimulated glucuronidation of dihydrotestosterone in MCF-7human breast cancer cellsrdquo Journal of Steroid Biochemistry andMolecular Biology vol 41 no 3-8 pp 579ndash582 1992

[81] D T Zava andW L McGuire ldquoAndrogen action through estro-gen receptor in a human breast cancer cell linerdquo Endocrinologyvol 103 no 2 pp 624ndash631 1978

[82] R Hackenberg I Turgetto A Filmer and K-D Schulz ldquoEstro-gen and androgen receptor mediated stimulation and inhibi-tion of proliferation by androst-5-ene-312057317120573-diol in humanmammary cancer cellsrdquo Journal of Steroid Biochemistry andMolecular Biology vol 46 no 5 pp 597ndash603 1993


[83] M Ni Y Chen E Lim et al ldquoTargeting androgen receptor inestrogen receptor-negative breast cancerrdquo Cancer Cell vol 20no 1 pp 119ndash131 2011

[84] L A Niemeier D J Dabbs S Beriwal J M Striebel and RBhargava ldquoAndrogen receptor in breast cancer expression inestrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiationrdquoModern Pathol-ogy vol 23 no 2 pp 205ndash212 2010

[85] S Park J Koo H S Park et al ldquoExpression of androgenreceptors in primary breast cancerrdquo Annals of Oncology vol 21no 3 Article ID mdp510 pp 488ndash492 2010

[86] J-C Pignon B Koopmansch G Nolens L Delacroix DWaltregny and R Winkler ldquoAndrogen receptor controls EGFRand ERBB2 gene expression at different levels in prostate cancercell linesrdquo Cancer Research vol 69 no 7 pp 2941ndash2949 2009

[87] I K Mellinghoff I Vivanco A Kwon C Tran J Wongvipatand C L Sawyers ldquoHER2neu kinase-dependent modulationof androgen receptor function through effects on DNA bindingand stabilityrdquo Cancer Cell vol 6 no 5 pp 517ndash527 2004

[88] S LuG Jenster andD E Epner ldquoAndrogen induction of cyclin-dependent kinase inhibitor p21 gene role of androgen receptorand transcription factor Sp1 complexrdquoMolecular Endocrinologyvol 14 no 5 pp 753ndash760 2000

[89] J P Garay B Karakas A M Abukhdeir et al ldquoThe growthresponse to androgen receptor signaling in ER120572-negativehuman breast cells is dependent on p21 andmediated byMAPKactivationrdquo Breast Cancer Research vol 14 no 1 article R272012

[90] T Visakorpi E Hyytinen P Koivisto et al ldquoIn vivo amplifica-tion of the androgen receptor gene and progression of humanprostate cancerrdquoNature Genetics vol 9 no 4 pp 401ndash406 1995

[91] Y Ogawa E Hai K Matsumoto et al ldquoAndrogen receptorexpression in breast cancer relationship with clinicopatholog-ical factors and biomarkersrdquo International Journal of ClinicalOncology vol 13 no 5 pp 431ndash435 2008

[92] E A Rakha M E El-Sayed A R Green A H S Lee JF Robertson and I O Ellis ldquoPrognostic markers in triple-negative breast cancerrdquo Cancer vol 109 no 1 pp 25ndash32 2007

[93] AM S Covaleda H Van den Berg J Vervoort et al ldquoInfluenceof cellular ER120572ER120573 ratio on the ER120572-agonist induced prolifer-ation of humanT47D breast cancer cellsrdquoToxicological Sciencesvol 105 no 2 pp 303ndash311 2008

[94] X Wu M Subramaniam S B Grygo et al ldquoEstrogen receptor-beta sensitizes breast cancer cells to the anti-estrogenic actionsof endoxifenrdquo Breast Cancer Research vol 13 no 2 article R272011

[95] M M Regan B Leyland-Jones M Bouzyk et al ldquoCYP2D6Genotype and tamoxifen response in postmenopausal womenwith endocrine-responsive breast cancer the breast interna-tional group 1-98 trialrdquo Journal of the National Cancer Institutevol 104 no 6 pp 441ndash451 2012

[96] A Z LaCroix R T Chlebowski J E Manson et al ldquoHealthoutcomes after stopping conjugated equine estrogens amongpostmenopausal women with prior hysterectomy a random-ized controlled trialrdquo Journal of the American Medical Associ-ation vol 305 no 13 pp 1305ndash1314 2011

[97] J S Lewis K Meeke C Osipo et al ldquoIntrinsic mechanism ofestradiol-induced apoptosis in breast cancer cells resistant toestrogen deprivationrdquo Journal of the National Cancer Institutevol 97 no 23 pp 1746ndash1759 2005

[98] J Baselga and S M Swain ldquoNovel anticancer targets revisitingERBB2 and discovering ERBB3rdquo Nature Reviews Cancer vol 9no 7 pp 463ndash475 2009

[99] S T Lee-Hoeflich L Crocker E Yao et al ldquoA central rolefor HER3 in HER2-amplified breast cancer implications fortargeted therapyrdquo Cancer Research vol 68 no 14 pp 5878ndash5887 2008

[100] S M Hill S A W Fuqua G C Chamness G L Greene andW L McGuire ldquoEstrogen receptor expression in human breastcancer associated with an estrogen receptor gene restrictionfragment length polymorphismrdquo Cancer Research vol 49 no1 pp 145ndash148 1989

[101] Q Cai X-O Shu F Jin et al ldquoGenetic polymorphisms inthe estrogen receptor 120572 gene and risk of breast cancer resultsfrom the Shanghai breast cancer studyrdquo Cancer EpidemiologyBiomarkers and Prevention vol 12 no 9 pp 853ndash859 2003

[102] L YaichWDDupont D R Cavener and F F Parl ldquoAnalysis ofthe PvuII restriction fragment-length polymorphism and exonstructure of the estrogen receptor gene in breast cancer andperipheral bloodrdquo Cancer Research vol 52 no 1 pp 77ndash831992

[103] T I Andersen K R Heimdal M Skrede K Tveit K Berg andA-L Borresen ldquoOestrogen receptor (ESR) polymorphisms andbreast cancer susceptibilityrdquoHuman Genetics vol 94 no 6 pp665ndash670 1994

[104] A Shin D Kang H Nishio et al ldquoEstrogen receptor alpha genepolymorphisms and breast cancer riskrdquo Breast Cancer Researchand Treatment vol 80 no 1 pp 127ndash131 2003

[105] A Forsti C Zhao E Israelsson K Dahlman-Wright J-AGustafsson andKHemminki ldquoPolymorphisms in the estrogenreceptor beta gene and risk of breast cancer no associationrdquoBreast Cancer Research and Treatment vol 79 no 3 pp 409ndash413 2003

[106] S L Zheng W Zheng B-L Chang et al ldquoJoint effect ofestrogen receptor120573 sequence variants and endogenous estrogenexposure on breast cancer risk in Chinese womenrdquo CancerResearch vol 63 no 22 pp 7624ndash7629 2003

[107] P Maguire S Margolin J Skoglund et al ldquoEstrogen receptorbeta (ESR2) polymorphisms in familial and sporadic breastcancerrdquo Breast Cancer Research and Treatment vol 94 no 2pp 145ndash152 2005

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


Table 1 Receptor-mediated effects and features in breast cancer

ER120572 ER120573 ER120572ER120573 heterodimer AR

ProliferationStimulates (in thepresence of E2 and

coactivators)

Suppresses but may dependon variant

(only ER1205731 binds E2 withhigh affinity)

Data support suppressionbut may depend on ER120573variant and density of each

receptor subtype


concurrent signalingpathways activated)

ApoptosisSuppresses (in thepresence of E2 and

coactivators)

Promotes (but may dependon variant)

Data support promotionbut may depend on ER120573variant and density of each

receptor subtype


concurrent signalingpathways or variant)

PR gene Activates Represses activation Represses activation mdashPrognostic factor Yes Uncertain but possible Uncertain but possible Uncertain but possible

ERE binding Yes Only ER1205731 120573ins and ER1205732bind ERE Yes Androgen response

element (ARE)Dimerization withER120572 and ER1205731 Yes Yes for wild type and 120573ins

ER1205732 binds ER120572 only mdash No

Receptor variants Best characterizedis hER-alpha36

At least 5(ER1205731 (wild type) delta518 aa insert (120573ins) ER120573cx

(ER1205732) and 1205735)

mdash

At least 7 splice variantshave been identified

(AR-V1 AR-V2 AR-V3AR-V4 AR-V5 AR-V6 andAR-V7) but many more

likely to existAF-2 Independent Dependent mdash mdashInteraction withother signalingpathways

Yes Yes Yes Yes

a protein receptor was identified as the critical component tomediate the broad repertoire of hormonal actions includingestrogen-stimulated growth of breast cancer cells [2] Whatlater became the target for new strategies to treat breastcancer the estrogen receptor (ER) was also on the vergeof being associated with the disease in two defining waysFirst as a predictive factor in that the ER emerged as thesingle most useful determinant to guide application of (andlikely response to) endocrine therapies [3] and second asa prognostic factor in that independent of treatment tumorcell expression of this hormone receptor was associated withimproved disease outcomes [4] More recently the ER hasbeen linked to two molecular subtypes of breast canceridentified as luminal A and luminal B [5] Further testingof ER-positive (ER+) tumors by analyzing expression ofa panel of genes resulted in groundbreaking informationfor managing women with early-stage hormone-dependentbreast cancer [6] Translated to a ldquorecurrence scorerdquo themultigene test had like ER both prognostic value (quantifiedthe risk of disease recurrence) and predictive value (estimatedthe benefit of adding chemotherapy)

These noteworthy attributes may have in large part pre-empted the potential importance of the second ER whichwas discovered less than two decades ago [7] Because of thisnew finding what was traditionally referred to as ER subse-quently became known as ER120572 Even though accumulatingdata suggest the more recently identified estrogen receptor(ie ER120573) may have biological and clinical relevance themajority of the published reports support the preeminenceof ER120572 even in tumor cells that coexpress both ER subtypes

While this conclusion is consistent with reports that breastcancer survival was not influenced by ER120573 expression inpatients with ER120572+ or ER120572-negative (ERminus) tumors [8 9]other investigators found a direct correlation between ER120573-positivity and overall survival [10] A confounding factor thatcould provide a partial explanation for this discrepancy is thevariable expression of one or more ER120573 variants in breastcancer (Table 1) Because of the potential clinical relevance ofER120573 a comprehensive discussion of this issue is provided inthe ER120573 section which follows later

Interestingly expression of the androgen receptor (AR)in primary breast tumors and metastatic lesions predatedthe discovery of ER120573 [11] However like ER120573 the clinicalsignificance of its presence in tumor cells remains uncertainNevertheless a number of studies suggest that the AR mayhave prognostic value independent of ER120572 expression Forexample even though AR is frequently present in ER120572+breast cancers AR has also been found in a significantpercentage of ER120572minus tumors [12 13] These observations maybe clinically relevant for the following reason Because tumorcell expression of ER120572 correlates with tumor size histologicgrade and axillary node metastasis it may be difficult toargue that the relatively good prognosis of ER120572+ breastcancers should be attributed in part to coexpressed ARHowever the finding that expression of AR in ER120572minus tumorswas associated with increased age postmenopausal statuslower tumor grade smaller tumor size and significantlyimproved disease-free survival suggests otherwise [13]More-over the absence of AR appeared to be associated with higherlevels of Ki-67 a cell proliferation marker Collectively these


(AB)

Gene

mRNA

Protein (domain)


ER1205731(wt)

Exons 1 2 3 4 5 6 7 8 9

(D) (E) (F)(C)

NH2 terminal (24)

DNA binding (96)


COOH terminal

AF-1

AF-1

AF-2

AF-2

3998400

(a)

Gene

Exons 1 2 3 4 5 6 7 8

mRNA

Protein (domain)

AR

(A) (D)(C)(B)

NTD DBD Hinge LBD

AF-1 AF-2

3998400

minusCOOHNHminus

2

(b)




3 Receptor Biology








H10

H6 H5

H9

H12

H11

H3


N terminus

C terminus

N terminus

H11H6

H3

N terminus

H3

H11C terminus

H6

H5 H5H2

H1

H4

H8

H7

HHHSERM

E2

(AB) (C) (D) (E) (F)

ER120572 AF1 AF2









CirculationE2

Target cell

SWISNF-ACoactivator


SERM


NCoR Corepressor

ERE ERE

Transcription

mRNA

No transcription


Nucleus

SRC-1

p300CBP

CARM1

SMRT

A B

Osteocalcin

ER120572
















AF-1 DBD LBDAF-2 F

bp 812-950 deleted

ER120572

ER1205731 (wt)

ER1205732

ER1205735

ER1205731205755

ER120573ins

Splice-variants

H


Nminus

Nminus

Nminus

Nminus

Nminus

Nminus

minusC

minusC

minusC

minusC

minusC

minusC














Adipose tissue

Adrenalgland

DHEA

4-dione

A-dione

Androsterone

Estrone

Aromatase

DHEA-S

Estradiol

Testosterone

Dihydrotestosterone

Aromatase

3120573-HSD

5120572-red

3120572-HSD

17120573-HSD1 7 12

5120572-red














6 Conclusion







References






























































120573) dif-




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















(AB)

Gene

mRNA

Protein (domain)


ER1205731(wt)

Exons 1 2 3 4 5 6 7 8 9

(D) (E) (F)(C)

NH2 terminal (24)

DNA binding (96)


COOH terminal

AF-1

AF-1

AF-2

AF-2

3998400

(a)

Gene

Exons 1 2 3 4 5 6 7 8

mRNA

Protein (domain)

AR

(A) (D)(C)(B)

NTD DBD Hinge LBD

AF-1 AF-2

3998400

minusCOOHNHminus

2

(b)




3 Receptor Biology








H10

H6 H5

H9

H12

H11

H3


N terminus

C terminus

N terminus

H11H6

H3

N terminus

H3

H11C terminus

H6

H5 H5H2

H1

H4

H8

H7

HHHSERM

E2

(AB) (C) (D) (E) (F)

ER120572 AF1 AF2









CirculationE2

Target cell

SWISNF-ACoactivator


SERM


NCoR Corepressor

ERE ERE

Transcription

mRNA

No transcription


Nucleus

SRC-1

p300CBP

CARM1

SMRT

A B

Osteocalcin

ER120572
















AF-1 DBD LBDAF-2 F

bp 812-950 deleted

ER120572

ER1205731 (wt)

ER1205732

ER1205735

ER1205731205755

ER120573ins

Splice-variants

H


Nminus

Nminus

Nminus

Nminus

Nminus

Nminus

minusC

minusC

minusC

minusC

minusC

minusC














Adipose tissue

Adrenalgland

DHEA

4-dione

A-dione

Androsterone

Estrone

Aromatase

DHEA-S

Estradiol

Testosterone

Dihydrotestosterone

Aromatase

3120573-HSD

5120572-red

3120572-HSD

17120573-HSD1 7 12

5120572-red














6 Conclusion







References






























































120573) dif-




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















H10

H6 H5

H9

H12

H11

H3


N terminus

C terminus

N terminus

H11H6

H3

N terminus

H3

H11C terminus

H6

H5 H5H2

H1

H4

H8

H7

HHHSERM

E2

(AB) (C) (D) (E) (F)

ER120572 AF1 AF2









CirculationE2

Target cell

SWISNF-ACoactivator


SERM


NCoR Corepressor

ERE ERE

Transcription

mRNA

No transcription


Nucleus

SRC-1

p300CBP

CARM1

SMRT

A B

Osteocalcin

ER120572
















AF-1 DBD LBDAF-2 F

bp 812-950 deleted

ER120572

ER1205731 (wt)

ER1205732

ER1205735

ER1205731205755

ER120573ins

Splice-variants

H


Nminus

Nminus

Nminus

Nminus

Nminus

Nminus

minusC

minusC

minusC

minusC

minusC

minusC














Adipose tissue

Adrenalgland

DHEA

4-dione

A-dione

Androsterone

Estrone

Aromatase

DHEA-S

Estradiol

Testosterone

Dihydrotestosterone

Aromatase

3120573-HSD

5120572-red

3120572-HSD

17120573-HSD1 7 12

5120572-red














6 Conclusion







References






























































120573) dif-




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















CirculationE2

Target cell

SWISNF-ACoactivator


SERM


NCoR Corepressor

ERE ERE

Transcription

mRNA

No transcription


Nucleus

SRC-1

p300CBP

CARM1

SMRT

A B

Osteocalcin

ER120572
















AF-1 DBD LBDAF-2 F

bp 812-950 deleted

ER120572

ER1205731 (wt)

ER1205732

ER1205735

ER1205731205755

ER120573ins

Splice-variants

H


Nminus

Nminus

Nminus

Nminus

Nminus

Nminus

minusC

minusC

minusC

minusC

minusC

minusC














Adipose tissue

Adrenalgland

DHEA

4-dione

A-dione

Androsterone

Estrone

Aromatase

DHEA-S

Estradiol

Testosterone

Dihydrotestosterone

Aromatase

3120573-HSD

5120572-red

3120572-HSD

17120573-HSD1 7 12

5120572-red














6 Conclusion







References






























































120573) dif-




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


























AF-1 DBD LBDAF-2 F

bp 812-950 deleted

ER120572

ER1205731 (wt)

ER1205732

ER1205735

ER1205731205755

ER120573ins

Splice-variants

H


Nminus

Nminus

Nminus

Nminus

Nminus

Nminus

minusC

minusC

minusC

minusC

minusC

minusC














Adipose tissue

Adrenalgland

DHEA

4-dione

A-dione

Androsterone

Estrone

Aromatase

DHEA-S

Estradiol

Testosterone

Dihydrotestosterone

Aromatase

3120573-HSD

5120572-red

3120572-HSD

17120573-HSD1 7 12

5120572-red














6 Conclusion







References






























































120573) dif-




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























Adipose tissue

Adrenalgland

DHEA

4-dione

A-dione

Androsterone

Estrone

Aromatase

DHEA-S

Estradiol

Testosterone

Dihydrotestosterone

Aromatase

3120573-HSD

5120572-red

3120572-HSD

17120573-HSD1 7 12

5120572-red














6 Conclusion







References






























































120573) dif-




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























6 Conclusion







References






























































120573) dif-




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















References






























































120573) dif-




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























































120573) dif-




























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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