Emerging Functional Roles of Nuclear Receptors in Breast Cancer

Home , ARNTL2, Estrogen receptor alpha, NPAS2, NR4A, PER3, Progesterone receptor A

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t b doan and others Nuclear receptors in 58: 3 R169–R190 Review breast cancer

Emerging functional roles of nuclear receptors in breast cancer

Tram B Doan, J Dinny Graham and Christine L Clarke Correspondence should be addressed Westmead Institute for Medical Research, Sydney Medical School – Westmead, University of Sydney, to T B Doan Sydney, New South Wales, Australia Email [email protected]

Abstract

Nuclear receptors (NRs) have been targets of intensive drug development for decades Key Words due to their roles as key regulators of multiple developmental, physiological and disease ff nuclear receptors processes. In breast cancer, expression of the estrogen and progesterone receptor remains ff breast cancer clinically important in predicting prognosis and determining therapeutic strategies. ff circadian clock More recently, there is growing evidence supporting the involvement of multiple nuclear ff metabolism receptors other than the estrogen and progesterone receptors, in the regulation of ff migration and metastasis various processes important to the initiation and progression of breast cancer. We review new insights into the mechanisms of action of NRs made possible by recent advances in genomic technologies and focus on the emerging functional roles of NRs in breast cancer biology, including their involvement in circadian regulation, metabolic reprogramming Journal of Molecular and breast cancer migration and metastasis. Endocrinology (2017) 58, R169–R190 Journal of Molecular Endocrinology Introduction

Breast cancer is the most common cancer diagnosed nearly all physiological aspects of life and the availability in women worldwide (Ferlay et al. 2015). Over the past of drugs targeting NRs that resulted from intensive drug decades, substantial progress toward treatment of primary development targeting NRs for a range of pathological estrogen receptor-positive (ER+) breast cancer has been conditions. The human NR superfamily consists of 48 made with the development of endocrine therapies highly evolutionarily conserved transcription factors with targeting the estrogen biosynthesis and signaling the ability to act as molecular sensors of physiological pathways. Despite the success of endocrine therapies, and environmental stimuli (Mangelsdorf et al. 1995). there remain subgroups of women for whom available Development of technologies that allow genome-wide, treatment offers little help. These include patients with unbiased profiling of genomic binding sites and gene ER+ breast tumors who develop endocrine treatment expression has allowed deeper insights into the molecular resistance (Dixon 2014), patients with estrogen receptor- mechanisms of NR actions. These studies highlight the negative (ER−) breast cancers (Hudis & Gianni 2011) complexity of gene regulatory networks governed by and cancers that recur in all age groups (EBCTCG 2005). NRs, the extensive nature of NR crosstalk and the role Women in these subgroups currently face the challenge of coregulators and the chromatin landscape of the cell of living with advanced disease; therefore, there exists as important modulators of NR cell type-specific and the need to develop rational treatments targeting these context-dependent function. subgroups of breast cancer. In the context of breast cancer, it is recognized that Nuclear receptors (NRs) are potential promising targets estrogen receptor (ESR1) and progesterone receptor (PGR) due to the importance of NRs as master regulators of play critical roles in the development and progression

10.1530/JME-16-0082 Journal of Molecular Endocrinology (AF1); theDNA-bindingdomain (DBD)consistingof The N-terminalA/Bdomain withactivationfunction1 Mangelsdorf 2014),whichconsistsoffourmajor domains: structuralorganization (Evans & evolutionarily conserved of theNRsuperfamilyareidentified throughtheirhighly acid andoxysterols(Mangelsdorf vitamins and cholesterol metabolites including retinoic for steroid hormones, thyroid hormones, lipophilic members. Thesetranscriptionfactorsincludethereceptors The humannuclearreceptorsuperfamilyconsistsof48 The nuclearreceptor superfamily genomic technologies. of actionNRsmadepossiblethroughadvances in as wellnewinsightsintothemolecularmechanisms these emergingfunctionalrolesofNRsinbreastcancer, and metastasis.Inthisreview, wewilldiscussevidencefor regulation ofthecircadian clock,metabolism,migration of breastcancertumorigenesisandprogressionincluding and that NRs are important regulators of several aspects involvement inregulatingproliferationandapoptosis involvement ofNRsinbreastcancerextendsbeyondtheir unexplored. Recentstudiesareestablishingthatthe the normalbreastandcancerhavelargelybeen of theremainingmembershumanNRfamilyin 2014). However, thefunctionalrolesofmajority 2002, al. et (RARB) inbreastcancer(Yang effect of the retinoic acid receptor beta the anti-migratory al.2009, et signaling (Hua the retinoicacidreceptoralpha(RARA)andestrogen considerable attention,particularlythecrosstalkbetween of theretinoidreceptorsubfamilyhavealsoreceived and anti-apoptoticeffectsinbreastcancer. Members have alsobeeninvestigatedfortheiranti-proliferative al.2011, et (GR) (Vilasco 2010, including thevitaminD3receptor(VDR)(Krishnan et al. 2015).Anumberofothernuclearreceptors, Barton et al. as apotentialtreatmenttarget(Cordera&Jordan2006, 2015), has emerged both as a marker of outcome and al.2010, et breasttumors(Park in primary androgen receptor(AR),whichisfrequentlyexpressed disease (Cordera&Jordan2006).Morerecently, the the estrogensignalingaxisarestandardofcareforER+ clinical managementprogramsandtreatmentstargeting and disease outcome.Consequently, measurementofESR1 breast tumorremainsthesinglemostrobustpredictorof of breastcancer, andmoreover, their expression ina DOI: 10.1530/JME-16-0082 http://jme.endocrinology-journals.org Review Review PGR expressioninbreastcancersisamainstayof 2013)andtheglucocorticoid receptor Mehta et al. t al.2010),and et Ross-Innes t al.2015b) et Abduljabbar t

b t al.1995).Members et

© 2017SocietyforEndocrinology doan andothers Printed inGreatBritain t al. et Flamini t al. et Grogg wide varietyofbiologicalprocesses innormalphysiology been showntoaffectthecell typespecificityofNRs. coregulators andthechromatin landscapeofthecellhave al. 2013).Boththeinteractionwith et RNAs (Millard factors, the chromatin landscape as well as non-coding target genesthroughinteractionswithothertranscription complexes thataffectNRtranscriptionalregulation of majority of coregulators function as members of large and includebothcoactivatorscorepressors.The to themechanismsbywhichNRsexerttheirfunctions conformation of the AF2 region. Coregulators are integral interaction ofNRswithcoregulatorsbyinfluencingthe Gronemeyer 2002, et al.2004). selective recognition by different NR subclasses (Laudet & this canonicalhormoneresponseelementallowfor repeats separatedbyaspacerwithvariablelength)of and duplications(organizedasdirect,invertedoreverted canonical hexamericsequenceRGGTCA.Modifications Nuclear receptorresponseelementsarederivativesofthe to increasebindingaffinity, specificityanddiversity. orphan receptors.Dimerizationisageneralmechanism heterodimerization partnersforVDR,THR,RARand heterodimers. RXRsinparticularcanactaspromiscuous THR, RARandRXRcanformbothhomodimers receptors generallybindashomodimers,whereasVDR, another familymember. Forexample,steroidhormone genes asmonomers,homodimersorheterodimerswith regionsoftarget response elementswithintheregulatory activation, NRsregulategenetranscriptionbybinding in circadian andmetabolic pathways(reviewedhere). inhuman,especiallyforNRsthatareinvolved observed ), whichpartiallyreflectthefunctionalgroupings (Fig. 1B of NRsintointegratedphysiologicfunctionalgroups NRs. In the mouse, this revealed a hierarchical organization feasible, basedonprofilingtheanatomicalexpressionof Organization ofNRsintofunctionalgroupingsisalso al.1999, et construction (Auwerx based onsequencealignmentandphylogenetictree groups 48 humanNRsareorganizedintosixevolutionary ligands fortheseNRshavenotbeenfound(Table 1). The designated asorphansbecauseendogenousphysiological 1A).ApproximatelyhalfoftheNRsare 1995) (Fig. 1986, (Giguere et al. have anAF2regionthatmediatescoactivatorinteraction ligand-binding domain(LBD),whichmayornot specificity andthehingeregionlinkingDBDto two zincfingermotifswhichconfersresponseelement breast cancer Nuclear receptorsin Published byBioscientifica Ltd. NRs regulatethetranscription ofgenesthatcontrola Ligand bindingalsoallostericallycontrolsthe In theclassicalmodelofNRaction,uponligand

1987, Kumar et al. Downloaded fromBioscientifica.com at09/27/202109:55:09AM t al.2006). et Germain 58 Mangelsdorf : 3 170 170 et al. via freeaccess PROOF ONLY

Review t b doan and others Nuclear receptors in 58:3 171 breast cancer

Figure 1 (A) Schematic diagram of the structural and functional organization of nuclear receptors (reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Drug Discovery (Gronemeyer et al. 2004), copyright 2004). The evolutionary conserved regions C and E are indicated as boxes (green and orange, respectively), and a black bar represent the divergent regions A/B, D and F. Domain functions are depicted above and below the scheme (AD, activation domain; AF1, activation function 1; NLS, nuclear localization signal). (B) Hierarchical clustering of NR tissue expression profile (reprinted from Cell, volume 126, Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM & Mangelsdorf DJ, Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network, pages 789–799, copyright (2006), with permission from Elsevier). The relationship between receptor expression, function and physiology is depicted as a circular dendrogram using the hierarchical, unsupervised clustering of NR tissue expression distribution profiles in mouse. The analysis reveals the existence of a higher order network tying nuclear receptor function to reproduction, development, central and basal metabolic functions, dietary-lipid metabolism and energy homeostasis. The NRs in red boxes are discussed in this review with a focus on their functional roles in circadian regulation, metabolism and breast cancer migration and metastasis.

including embryonic development, reproduction, also observed by Lin and coworkers (Lin et al. 2015). metabolism, homeostasis and cell proliferation. NRs In addition to ESR1, PGR and AR, expression levels of other are also known to play a role in various pathological NRs were shown to be associated with histological grade Journal of Molecular Endocrinology processes including cancer, inflammation and metabolic (THRB, NUR77, RORC, COUP-TF2 and LRH-1), to classify disorders (McKenna & O’Malley 2010) and as such have breast tissues (THRA, ESR1, NURR77, EAR2 and RARG) and been targets of intensive drug development for decades to predict metastasis-free survival in tamoxifen-treated (Ottow & Weinmann 2008). patients (THRB, COUP-TF2, MR and PPARG). Thirty-three of the 48 human NRs were also observed to be expressed NR expression in the normal breast and in stromal cells and four of these (RORA, THRB, VDR and breast cancer PPARG) were shown to have differential expression profiles in cancer-associated fibroblasts compared to normal Recent studies have begun to provide a global view of the breast adipose fibroblasts (Knower et al. 2013). Together, functional roles and expression of the NR superfamily these studies highlight that multiple members of the NR in primary normal breast (Muscat et al. 2013) and family are likely to play important roles in breast cancer breast cancer tissues (Muscat et al. 2013, Lin et al. 2015). growth and development and to have discriminant and Muscat and coworkers found that the majority of NRs prognostic value in breast cancer. are expressed in the breast (41 of 48). Many NRs showed differential expression in breast cancer compared to the NR expression in breast cancer subtypes normal breast indicative of potential involvement in breast cancer biology (Muscat et al. 2013). In particular, Breast cancer is a heterogeneous disease encompassing breast cancer is associated with the overexpression of the multiple subtypes with distinct molecular profiles, NR4A subgroup as well as EAR2, and pan-repression of therapeutic response and clinical outcomes (Prat et al. the majority of NRs relative to the normal breast. High 2015). Several NRs have been shown to either act expression of the NR4A subgroup in breast cancer was co-operatively with ESR1 and/or have differential

Steroid hormonereceptors

Orphan nuclearreceptors

Non-steroid hormonereceptors Name Table 1

Adopted orphans Estrogen receptor Tailess-related receptor Testicular orphanreceptors Hepatocyte nuclearfactor4 Short heterodimericpartner DSS-AHC criticalregiononthe Steroidogenic factor-like Retinoid Xreceptor Vitamin Dreceptor-like Liver Xreceptor-like Rev-erbs RAR-related orphanreceptor Thyroid hormonereceptor 3-Ketosteroid receptor Chicken ovalbuminupstream Photoreceptor cell-specific Peroxisome proliferator- Vitamin Dreceptor Retinoic acidreceptor DOI: 10.1530/JME-16-0082 http://jme.endocrinology-journals.org Review Review X chromosome,gene1 promoter-transcription factor receptor activated receptor Human nuclearreceptors. Nomenclature NR1A2 NR3A1 NR2E1 NR2C2 NR2C1 NR2A2 NR2A1 NR0B2 NR0B1 NR5A2 NR5A1 NR2B3 NR2B2 NR2B1 NR1I3 NR1I2 NR1H4 NR1H3 NR1H2 NR1D2 NR1D1 NR1C3 NR2F2 NR1C2 NR1F2 NR1F1 NR1B3 NR1B2 NR1A1 NR3C4 NR3C3 NR3C2 NR3C1 NR2F1 NR2E3 NR1C1 NR1I1 NR1F3 NR1B1 NR3A2 t

© 2017SocietyforEndocrinology doan andothers Printed inGreatBritain Symbol THRB ESR1 TLX TR4 TR2 HNF4g HNF4a SHP DAX-1 LRH-1 SF-1 RXRG RXRB RXRA CAR PXR FXRa LXRa LXRb REV-ERBb REV-ERBa PPARG PPARD RORB RORA RARG RARB THRA AR PGR MR GR COUP-TF1 PNR PPARA VDR RORC RARA ESR2 COUP-TF2 Entrez ID 10062 10002 7068 2099 7101 7182 7181 3174 3172 8431 2494 2516 6258 6257 6256 9970 8856 9971 7376 9975 9572 5468 5467 6096 6095 5916 5915 7067 5241 4306 2908 7025 5465 7421 6097 5914 2100 7026 367

breast cancer Nuclear receptorsin

Published byBioscientifica Ltd. Ligands Thyroxine (T Estogens Not known All-trans retinoicacid All-trans retinoicacid Fatty acids Fatty acids CD437 retinoids Not known Phospholipids Phospholipids 9-cis-retinoic acid 9-cis-retinoic acid 9-cis-retinoic acid Androstanol, Bile acids Bile acids Oxysterols Retinoic acid Heme Heme Fatty acids Fatty acids Cholesterol, cholesteryl Oxysterols All-trans and9-cis All-trans and9-cis Thyroxine (T Testosterone, Progesterone Aldosterone Cortisols Not known Benzimidazoles Fatty acids Calcitriol (1′,25 Retinoic acid All-trans and9-cis Estradiols Retinol/ATRA androstenol sulphate retinoic acid retinoic acid dihydrotestosterone (hydrocortisone) dihydroxy vitaminD3) retinoic acid triiodothyronine (T triiodothyronine (T 4 4 ), ),

3 3 ) ) Downloaded fromBioscientifica.com at09/27/202109:55:09AM vs normal Expression inBC Decreased Decreased Increased Not expressed Decreased Decreased Decreased Not expressed Not expressed Not expressed Decreased Not expressed Decreased Decreased Decreased Not expressed Decreased Not expressed Decreased Decreased Decreased Decreased Decreased Decreased Decreased Decreased Decreased Decreased Increased Expressed inBC Decreased Increased Decreased Decreased Decreased Decreased Decreased Decreased Increased Decreased 58 : 3 ESR1 expression Association with Yes Yes Yes

Yes Yes

Yes Yes Yes

Yes Yes Yes Yes

a,b a,b a,b a,b a,b a,b b b b b (Continued) 172 172 via freeaccess PROOF ONLY

Review t b doan and others Nuclear receptors in 58:3 173 breast cancer

Table 1 Continued.

Expression in BC Association with Name Nomenclature Symbol Entrez ID Ligands vs normal ESR1 expression ErbA2-related gene 2 NR2F6 EAR2 2063 Not known Increased Estrogen receptor-related NR3B1 ESRRA 2101 Isoflavones, Decreased receptor diethylstilbestrol, chlordane NR3B2 ESRRB 2103 Isoflavones, Decreased diethylstilbestrol, 4-hydroxy tamoxifen NR3B3 ESRRG 2104 Isoflavones, Decreased Yesb diethylstilbestrol, 4-hydroxy tamoxifen Nerve growth factor IB-like NR4A1 NUR77 3164 Cyclosporone-B, Increased diindolylmethane analogs NR4A2 NURR1 4929 6-Mercaptopurine, Increased benzimidazoles, C-DMIs NR4A3 NOR1 8013 6-Mercaptopurine, Increased prostaglandin A2 Germ cell nuclear factor NR6A1 GCNF 2649 Not known Decreased

aMuscat et al. (2013); bLin et al. (2015).

actions in ER+ vs ER− breast cancers. For instance, AR Similarly, the expression of GR has been shown has different roles in ER+ vs ER− breast cancers. AR has to be differentially associated with survival in been investigated extensively as a therapeutic target in ER+ vs ER− breast cancers. In ER+ breast cancers, ER− breast cancer. It was reported that in ER−/HER2+ high GR expression is associated with better survival breast tumors, AR stimulates oncogenic Wnt and HER2 (Pan et al. 2011, Abduljabbar et al. 2015b), whereas in signaling pathways thereby stimulating cancer cell ER− breast cancers, high GR expression is correlated with growth (Ni et al. 2011). However, the role of androgen poorer breast cancer-specific survival (Pan et al. 2011, signaling in ER+ breast cancer is less clear. Expression of Abduljabbar et al. 2015b). AR is associated with good prognosis in ER+ breast cancer Recent studies profiling the expression of NRs in Journal of Molecular Endocrinology (Hu et al. 2011, Hilborn et al. 2016), with anti-estrogenic ER+ and ER− cancers have also identified other NRs and anti-proliferative effects in ER+ breast cancer being whose expression levels differ significantly between ER+ reported (Peters et al. 2009, D’Amato et al. 2015). The and ER− breast cancers (Table 1). In particular, AR, PGR, anti-proliferative effect of AR is partly attributed to its PNR, RARA and THRB were reported to be significantly inhibitory effect on ESR1 signaling in ER+ breast cancer differentially expressed between ER+ and ER− breast cells (Peters et al. 2009, Fioretti et al. 2014). However, AR cancers (Muscat et al. 2013) and significantly associated has also been reported to contribute to therapy resistance with ESR1 expression (Lin et al. 2015). The expression of in ER+ breast cancer cells overexpressing AR, with increase DAX-1, LRH-1, PPARA, RORB, RORC and TLX were also in AR-to-ESR1 ratio associated with worse outcome for reported to be significantly associated with ESR1 expression tamoxifen-treated patients (Cochrane et al. 2014) and in multiple microarray datasets (Lin et al. 2015). increased agonist activity of Tam in AR overexpressing cells. In this context, AR reportedly increased tamoxifen Mechanisms of NR action agonist activity via the activation of EGFR in ER+ breast cancer, and this was blocked by dual treatment with the Alterations in normal transcriptional programs are anti-androgen enzalutamide and EGFR inhibitor gefitinib a fundamental feature of cancer pathogenesis and (Ciupek et al. 2015). In addition, AR appears to promote progression. Nuclear receptors are important regulators proliferation of molecular apocrine breast cancer; a that directly couple small-molecule signaling with subset of TNBC expressing AR, through activation of transcriptional regulation. An understanding of their genes that are normally regulated by ESR1 in ER+ cancer mechanisms of action at the genomic and network level, (Robinson et al. 2011). and how these processes are altered in breast cancer, is of

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0082 Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 09:55:09AM via free access Journal of Molecular Endocrinology genomic action in which NRs frequently act on long-range genomic actioninwhichNRs frequentlyactonlong-range these studiessuggestamore complexmodelofNR chromatin interactions (Liu & Cheung 2014 ). Together, by studiesontheestrogen receptor-mediated long-range regulation thatinvolveschromatin loopingasillustrated NRs arecapableofmediatinglong-rangetranscriptional 2011).Furthermore, intestinal epithelialcells(Surjit et al. confers transactivationtoligandedGRinepidermisand canonical glucocorticoidresponseelements(GRE)that (nGRE) thatconferstransrepressioninadditiontothe (GR) iscapableofbindinganegativeresponseelement responses ofNR.Forexample,theglucocorticoidreceptor elements can be a mechanism to fine tune transcriptional ( in ameta-analysisofNRcistromesdifferentcelltypes canonical motifandhalf-siterecognitionisalsoconfirmed but alsotodistalregionsandtheprevalenceofnon- that NRslocalizenotonlytoproximalpromoterregions al.2013).Theobservation et (Kittler NRs beingobserved localization, withbothproximal-biasedanddistal-biased and foundthatNRvariedsignificantlyintheirgenomic distribution ofthebindingsites24NRsinMCF-7cells 2006). Kittlerandcoworkersexaminedthegenomic not contain the canonical ESR1-binding motif (Carroll et al. distal regionsofthegenomeandthatmanyESR1sitesdid cancer celllineshowedthat most ESR1binding occurs at mapping ofESR1genomiclocalizationintheMCF-7breast or ChIP-Seq. In the context of breast cancer, genome-wide nuclear receptors and transcription factors using ChIP-chip that profiled the genome-widebinding sites ofseveral classical modelshavebeenchallengedbyrecentstudies orientation (Mangelsdorf recognition ofstringentpairedhalf-siteswithhighlyspecific bind proximallytothepromotersoftargetgenes,through hormone-responsive genesgaverisetothemodelthatNRs Traditionally, studiesonnuclearreceptoractionat Shifts from the‘classical’modelofNRaction in breastcancermadepossiblebythesegenomic methods. section, wereviewnewinsightsofNRmechanismsaction networksinbreastcancer.receptor regulatory Inthissub- nuclear receptorsandhighlightthecomplexityof revealed newinsightsintothemechanismsofaction wide manner. Studiesemployingthesemethodshave genomic locationsofNRbindinginanunbiased,genome- chip, ChIP-SeqandGRO-Seqhasenabledprofilingofthe cancer development. fundamental importancetoourunderstandingofbreast ). NR binding at non-canonical response 2011).NRbindingatnon-canonicalresponse Tang et al. DOI: 10.1530/JME-16-0082 http://jme.endocrinology-journals.org Review Review The developmentoftechnologiessuchasChIP- t al.1995).However, these et t

with PGR-bindingsitesthat showstrongnucleosome occurs, and progesterone-responsive genesare associated nucleosomes containingfunctional PGR-bindingsites occupancy. Upon hormonetreatment,remodelingof with DHSregionsthatstill exhibithighnucleosome that PGRbindinguponhormonestimulationcorresponds (MNase) followedbynext-generationsequencingshowed Profiling ofthePGRbyDNaseandMicrococcalnuclease al. 2013). et affinity estrogenresponseelements(Gertz characterized byinaccessiblechromatincontaininghigh- ESR1-binding sitessharedbymultiplecelltypesare correspond tocelltype-specificgeneregulation,whereas co-occurrence ofothertranscriptionfactorbinding,and binding sitescoincidewithpre-existingopenchromatin, ESR1 revealedasimilarpattern.ThemajorityofESR1- al. ). Profilingof 2015 et range interactions(Kuznetsova the formationofactiveenhancersandincreasedlong- subset of sites containing the consensus GRE results in occurs atpre-accessiblechromatin.BindingofGRtoa that, similartobreastcells,themajorityofGRbinding and afterdexamethasoneinductioninHeLacellsfound 2011). Arecentstudyoflong-rangeinteractionsbefore al. et hormone-induced remodeledchromatin(John DHS sites,whereasonly~20%ofGRbindingoccursat majority (>70%)ofGRbindingoccursatpre-induction hypersensitive sites(DHS)inbreastcellsrevealedthatthe of NRaction.Genome-widescreeningDNAseI induction vspost-inductionchromatinasadeterminant several groupshaveinvestigatedthequestionofpre- conformational changes induced uponligand binding, widely accepted model of NR binding to DNA only after cell type-specifictranscriptionalregulation.Duetothe NR–chromatin interactionisamajordeterminantofNR regulates aswellisregulatedby, NRactions,andthat existing inadynamiccontinuumofcondensationstates, landscape ofthecell.Itisbecomingclearthatchromatin, and complexinteractionsbetweenNRthechromatin through advancesingenomictechnologiesisthedynamic section), anothermajoraspectofNRactionilluminated transcriptional responseofNRs(discussedinthenext of coregulatorsindeterminingthecelltype-specific Clarke &Graham2012).Inadditiontotheinfluence 2008, of thesameNRindifferentcelltypes(Krum et al. remarkable differenceinthegenome-widebindingprofiles Studies investigatingNRcistromeshighlightthe Cell typespecificityandthechromatin landscape of differentresponseelements. enhancers whoseactionscanbefine-tunedbyrecognition breast cancer Nuclear receptorsin Published byBioscientifica Ltd.

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Review t b doan and others Nuclear receptors in 58:3 175 breast cancer

remodeling upon hormone induction (Ballare et al. 2013). SRC to E2-stimulated genes while the absence of SRC The chromatin landscape of the cell therefore plays an was observed at E2-repressed genes (Kininis et al. 2007). important role in determining the genomic binding In a subsequent study, Zwart and coworkers mapped the profiles of specific NRs. Although some NRs such as genome-wide binding sites of several ESR1 coregulators ESR1and GR rely mostly on pre-programmed sites made (SRC1, SRC2, SRC3, p300 and CBP) in MCF-7 cells and accessible by other cell- and tissue-specific pioneer DNA- showed a complex network of ESR1-coregulator binding, binding factors, other NRs such as PGR require ligand- with preferential binding sites for each coregulator. dependent active chromatin remodeling. They identified a subset of ESR1-regulated genes that are co-occupied by SRC3, but not SRC1 or SRC2, that predicts poor or good survival outcome depending on whether Pioneer factors and coregulators as modulators of the genes were upregulated or downregulated (Zwart et al. NR function 2011). Lupien and coworkers also identified association Pioneer factors are transcription factors that can bind between a subset of E2-induced ESR1 binding sites condensed chromatin and influence transcription by co-occupied by CARM1 and gene repression, independent facilitating subsequent recruitment of other transcriptional of the presence of FOXA1 binding. They also identified regulators. Recent studies have highlighted the importance another subset of E2-induced, FOXA1-independent, ESR1 of pioneer factors in facilitating chromatin accessibility and and CARM1 co-occupied sites that result primarily in also in determining the cell type-specific response of NRs. repression of expression (Lupien et al. 2009). These studies This is exemplified by the dependence of ESR1 on FOXA1 demonstrate that selective interaction with different in breast cancer. FOXA1 expression is luminal restricted coregulators at specific subsets of target genes may be an (Perou et al. 2000) and is thought to function as a pioneer important mechanism through which the specificity of factor (Cirillo et al. 2002). FOXA1 has been observed to NR action is modulated. influence genome-wide chromatin accessibility and is Due to their central role in regulating NR-mediated a key determinant of cell type-specific ESR1 genomic transcription, many coregulators are known to be localization (Lupien et al. 2008, Hurtado et al. 2011), involved in human diseases (Lonard et al. 2007, Lonard reflecting the importance of interaction with other factors & O’Malley 2012). In the breast, changes in expression on control of cell specificity of ESR1. Similarly, AP-1 has levels of coregulators have been implicated in the tissue- been shown to recruit GR to regions of the genome that specific response to tamoxifen (Keeton & Brown 2003). are basally accessible prior to hormonal treatment. AP-1 The majority of coregulators show differential expression

Journal of Molecular Endocrinology is thought to maintain chromatin accessibility for GR between breast cancer and normal breast tissues, as well as binding as well as recruiting GR indirectly in the absence between ER+ and ER− breast cancers. This is accompanied of a canonical GR motif (Biddie et al. 2011). by changes in the expression correlations between subsets In addition to pioneer factors, coregulators interact of coregulators and specific NRs, whose expression showed with NRs and other transcription factors to facilitate prognostic value in breast cancer (Doan et al. 2014). transcription of target genes. According to the Nuclear Coregulators are therefore critical determinants of Receptor Signaling Atlas (NURSA: www.nursa.org), there NR-mediated transcriptional regulation in the breast and are 320 NR coregulators identified to date. However, this disruptions in the normal NR–coregulator interaction number is likely to be a gross underestimation according network are potentially an important aspect of breast to a recent proteomic study (Malovannaya et al. 2011). cancer biology. Coregulators can assist in transcriptional regulation of NRs by facilitating chromatin accessibility, stabilizing Combinatorial control of gene expression by NRs in NR–DNA interaction or facilitating indirect NR–DNA breast cancer interaction through tethering (McKenna & O’Malley 2002, Millard et al. 2013). Recent large-scale integrative analyses of transcription Selective recruitment of coregulators to subsets of factor genomic localization data from the ENCODE NR-binding sites can also be a mechanism through which project highlighted the extraordinary complexity of transcriptional regulation of subsets of NR target genes are transcriptional regulation and the extensive functional fine-tuned. An early study of ESR1 and steroid receptor crosstalk between transcription factors (ENCODE Project coactivator protein (SRC) binding using promoter tiling Consortium 2012, Gerstein et al. 2012, Xie et al. 2013). arrays showed E2-dependent recruitment of ESR1 and This observation also holds for NR in breast cancer.

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0082 Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 09:55:09AM via free access Journal of Molecular Endocrinology ESR1-binding events,resulting inageneexpressionprofile shown to be recruited to the ESR1 complex and to redirect presence ofbothestrogen and progesterone,PGRwas share genomicbindingsites withPGRandLRH-1.Inthe between theseNRs. time, targetandcell-specificmodesofco-operation co-operative andantagonistic,perhapsreflectingdifferent GR, thenatureoftheirinteractionisreportedtobeboth ESR1 co-occupies many target genes with RARA as well as 2013).Therefore,although target genes(Karmakar et al. estrogen receptor-mediatedtranscriptionalactivation of with displacementofESR1leadingtotherepression of dexamethasone, GRrecruitmenttothesesitesisassociated several ESR1-bindingsitesincellstreatedwithbothE2and MCF-7 cellsrevealedthat,althoughGRco-occupies study profilingESR1andGRgenomiclocalizationin 2013). Another to DNAfortheotherNR(Miranda et al. facilitates chromatinremodelingtherebyenablingaccess assisted loadingmechanism,inwhichbindingofoneNR significant co-operationofthesetwoNRs,throughan epithelialcelllinesrevealed and GRinmousemammary Innes or co-operativeisstillcontroversial(Hua profiles, althoughwhethertheinteractionisantagonistic similarbinding showed thatESR1andRARAsharevery (Fontana et al. 1992).StudiesofESR1andRARAcistromes and antagonizethegrowthstimulationeffectofestrogen been knowntoinhibitproliferationinbreastcancercells action in breast cancer cells. For example, retinoic acid has including otherNRs,areimportantdeterminantsofESR1 not act on its own and that other transcription factors, tumors. Mounting evidence indicates that ESR1 does to drive growth and proliferation in the majority of breast comparing theoverlapoftheircistromes.ESR1isknown various other NRs in breast cancer cells by individually convergence ingenomicbindingbetweenESR1and regionsinbreastcancercells. active regulatory relevant genesandarehypothesizedtobeimportant These regions are also enriched with breast cancer- chromatin marksandincreasedaccessibility. elements,includingactive with activeregulatory These HOTregionsareenrichedwithfeaturesassociated coordinately occupiedbymultipleNRs(HOTregions). connected andtherearemanyregionsinthegenome They showedthattheresultingnetworkishighlyinter- associated coregulators in MCF-7 breast cancer cells. map fromcistromicdataof24NRsand14breastcancer- Kittler and coworkers (Kittler DOI: 10.1530/JME-16-0082 http://jme.endocrinology-journals.org Review Review In additiontoRARAandGR, ESR1wasreportedto On asmallerscale,otherstudieshavealsorevealed t al.2010).Likewise,cistromicprofilingofESR1 et et al. 2013)builtaregulatory t

© 2017SocietyforEndocrinology doan andothers et al. 2009, Printed inGreatBritain Ross- change inESR1actionwas showntobeinfluencedby in sampleswithdifferent outcomes.Thisdynamic process, withdistinctESR1-binding regionsobserved they showedthatESR1binding isahighlydynamic insampleswithgoodprognosis.Further,was observed metastatic samples,whereaslowerESR1signalintensity highsignalintensityatESR1-binding sitesin observed al.2012).They et and cancerprogression(Ross-Innes to directlyexplorethecorrelationbetweenESR1binding seq ofESR1inclinicalsampleswithdifferentprognoses outcomes. Ross-InnesandcoworkersperformedChIP- with breastcancerdiseaseprogressionandclinical in NRtranscriptionalprogramsandtheirassociation Recent studieshavehighlightedtheeffectofchanges type-specific changesinPGRtranscriptionalregulation. Graham 2012),reflectingcancer-associatedandcell breast cellsdisplayremarkablylowoverlap(Clarke& breast cancer cells and AB-32 immortalized normal profiles. ThetranscriptionaltargetsofPGRin T-47D disease-associated shiftsintheirgenomicbinding factors displayingtemporal,celltypespecificand regulation isahighlydynamicprocesswithtranscription It isbecomingincreasinglyevidentthattranscriptional Reprogramming ofNRbinding anddiseaseprogression have thepotentialtoleadnoveltherapeuticstrategies. the functionalinteractionsbetweenNRsinbreastcancer is stilltobedetermined;nevertheless,theseinsightsinto supporting thisasamechanismcommontootherNRs particularly a feature of ER or whether data will emerge studies sofarreflecttranscriptionalplasticitythatis analyses in unraveling this complexity. Whether the networks andtheutilityofintegrated,genome-wide particularly betweenERandotherNRs,ingeneregulatory responsive genesinMCF-7cells(Lai et al.2013). of ESR1andsynergisticallyregulateasubsetestrogen- substantial portion(~35%)ofitsbindingsiteswiththat are yettobeestablished.LRH-1wasreportedsharea line models,andtheimplicationsforbreastcancerinvivo Furthermore, themajorityofdataarederivedfromcell PGR andtheircrosstalkarehighlycontextdependent. (Daniel et al. 2015).ItislikelythattheactionofESR1and in amoreaggressiveproliferativeresponsetoestrogen transcriptional complexwithESR1andPELP1,resulting by actingasamolecularscaffoldfortheformationof un-liganded PGRBactivatedasubsetofERtargetgenes 2015). However, inthepresenceofestrogenalone, associated withbetterclinicaloutcome(Mohammed et al. breast cancer Nuclear receptorsin Published byBioscientifica Ltd. These studies highlight the complexityof cross talk,

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Review t b doan and others Nuclear receptors in 58:3 177 breast cancer

the action of other NRs, such as PGR (Mohammed et al. Emerging functional roles of NR in BC 2015), as well as the signaling context leading to It is now clear that a number of NRs are implicated in ESR1 activation. For example, ESR1 displayed distinct breast cancer growth and development (Conzen 2008). It genomic binding profiles depending on whether ESR1 is emerging that, in addition to influencing cell growth was activated by estrogen or through the epidermal and proliferation, NRs also play important roles in other growth factor (EGF) pathway (Lupien et al. 2010). The aspects of breast cancer biology. Table 2 summarizes EGF-induced ESR1 cistrome specifically regulates genes reported involvement of NRs in selected aspects of breast that are overexpressed in ERBB2-positive breast cancers cancer biology. This section outlines some of the emerging and associated with poor clinical outcomes. The EGF functional roles of NRs in breast cancer. pathway can therefore be an alternative activator for ESR1 signaling in breast cancer and provides a molecular explanation for the endocrine therapy resistance often Nuclear receptors as key components of the seen in ER+ERBB2+ breast cancers. Analysis of ESR1 and circadian clock ESRRA cistromes in tamoxifen-sensitive vs -resistant breast cancer cells showed that despite regulating A circadian rhythm is any biological process that displays distinct transcriptional networks, their cistromes are an endogenous, entrainable oscillation cycle of roughly reprogramed in tamoxifen-resistant breast cancer cells 24 h, driven by a self-sustained timekeeping mechanism, toward the regulation of genes functionally relevant the circadian clock. The circadian clock governs many to resistance (Thewes et al. 2015). These studies show aspects of human physiology, including body temperature, that NR binding profiles can be shifted in a context- sleep–wake cycle, blood pressure, hormone secretion and dependent manner, resulting in altered transcriptional metabolism. In line with this, at least 10% of all genes networks that affect disease progression and outcome. are under the control of the circadian system and display

Table 2 NR function in breast cancer.a

Pro-oxidative Circadian Anti-proli Pro- Anti- phosphoryla- Pro- Anti- Pro- Pro- involve- Nomenclature Symbol ferative apoptotic migratory tion proliferative apoptotic migratory glycolytic ment NR3A1 ESR1 Y Y Y NR3A2 ESR2 Y Y Y NR3C1 GR Y Y Journal of Molecular Endocrinology NR3C3 PGR Y Y Y Y NR3C4 AR Y Y NR1B1 RARA Y Y NR1B2 RARB Y Y Y NR1B3 RARG Y Y NR1F1 RORA Y NR1F2 RORB Y NR1F3 RORC Y NR1I1 VDR Y Y NR1C1 PPARA Y NR1C2 PPARD Y NR1C3 PPARG Y Y Y Y NR1D1 REV-ERBa Y Y Y NR1D2 REV-ERBb Y Y Y NR2B1 RXRA Y NR2B2 RXRB Y NR2B3 RXRG Y NR2F1 COUP-TF1 Y NR2F2 COUP-TF2 Y NR3B1 ESRRA Y Y NR3B3 ESRRG Y Y NR4A1 NUR77 Y

aNR effect on cancer-related biological processes based on studies in breast primary tissue or cell lines. The influence of NR on breast cancer proliferation, apoptosis, migration, metabolism as well as involvement in circadian regulation/response is tabulated. Y, indicates reported involvement.

© 2017SocietyforEndocrinology doan andothers 2003, Oishi et al. Printed inGreatBritain (Zhao et al. 2014). display circadian expression in various metabolic tissues circadian clockisextensive,withatleast35NRsknownto The listofotherNRspotentiallyundercontrolthe al. 2011). et al.2010)andESRRA(Dufour et Campbell by thecircadian clock,mostnotablyGR(Conway- have beenshowntoregulateaswellbeingregulated (Preitner et al.2002). machinery the pivotalroleofREV-ERBs intheuniversal circadian deletion studies and cistrome analyses have confirmed of clockgeneexpression(Akashi&Takumi 2005).Gene have demonstratedtheirimportanceintheregulation elementsasREV-ERBs,regulatory andarangeofstudies breast cancer Nuclear receptorsin Published byBioscientifica Ltd. In additiontoREV-ERBs andRORs,severalotherNRs

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Review t b doan and others Nuclear receptors in 58:3 179 breast cancer

To date, epidemiological studies reported mixed ESR1 has been shown to be an important regulator findings on the association between increased risk of linking the circadian system and breast cancer breast cancer and circadian disruption in the form tumorigenesis, acting as a regulator of (as well as being of night shift work. Although a few studies reported regulated by) the core clock genes. ESR1 appears to no significant association between breast cancer and participate in a feedback loop involving the clock protein night work (O’Leary et al. 2006, Pronk et al. 2010), PER2, which was shown to be a tumor suppressor in the majority of recent studies reported significant or luminal breast cancer. Although PER2 is E2 inducible, borderline associations, with the strongest association PER2 itself is thought to mediate ESR1 degradation found with long-term exposure to night work (Hansen through the proteasome pathway. Suppression of PER2 2001, Schernhammer et al. 2001, 2006, Hansen & Lassen leads to ESR1 stabilization (Gery et al. 2007). In addition, 2012, Hansen & Stevens 2012, Knutsson et al. 2013, ESR1 was shown to bind estrogen response elements in the Menegaux et al. 2013, Rabstein et al. 2013, Akerstedt et al. promoter region of CLOCK leading to the upregulation 2015, Papantoniou et al. 2015). Meta-analysis studies have of CLOCK in breast cancer cells. Knockdown of CLOCK also reported a positive association between night work attenuated proliferation in breast cancer cells (Xiao et al. and breast cancer risk (Jia et al. 2013) and that a positive 2014). Therefore, CLOCK appears to be an important dose–response gradient is observed for breast cancer with mediator of the proliferative effect of E2 in breast cancer. increased years of night shift and cumulative night work In summary, NRs play important regulatory roles in (Wang et al. 2013). both the universal and tissue-specific circadian systems. Although circadian disruption is prominently linked In particular, REV-ERBs and RORs are integral regulators to breast cancer tumorigenesis through epidemiological of the universal circadian clock, and various other NRs studies, the molecular mechanisms and NRs involved exhibit circadian expression. Although epidemiological are still largely unknown, with most published studies studies have linked circadian disruption and breast cancer focusing on the ESR1 as a link between the circadian system tumorigenesis, a lot remains to be learned about the and breast cancer development. Many studies suggest that underlying molecular mechanism. Lowered melatonin lowered melatonin level due to exposure to night light due to night light exposure is thought to play a role and contributes toward breast cancer development and drug there is evidence supporting the involvement of ESR1 resistance. Melatonin is thought to exert its oncostatic as an integral regulator linking circadian regulation and effect through multiple mechanisms including anti- breast cancer development. mitosis, anti-angiogenesis, anti-oxidation and regulation

Journal of Molecular Endocrinology of immune response (Viswanathan & Schernhammer Regulation of energy metabolism 2009). The oncostatic effect of melatonin in breast cancer is thought be mediated through its anti-estrogenic actions As the initial observation by Warburg that proliferating as well as its role in regulating the activity of aromatases, tumor cells converted the majority of their glucose to the enzymes responsible for the local biosynthesis of lactate even in oxygen-rich condition and his hypothesis estrogens from androgens (Cos et al. 2006). Recent studies that altered metabolism is a characteristic of cancer using MCF-7 breast cancer xenografts in mice showed cells, metabolic reprogramming has now attained cancer that suppression of melatonin production by dim light hallmark status (Ward & Thompson 2012). Specifically, exposure at night leads to both tamoxifen (Dauchy et al. the Warburg effect describes a shift toward aerobic 2014) and doxorubicin resistance (Xiang et al. 2015). glycolysis in preference to oxidative phosphorylation as In addition to the effect of melatonin, there is the major means of ATP generation in cancer cells, even evidence linking the core clock genes as well as the REV- in oxygen-rich conditions. Although aerobic glycolysis ERBs with breast cancer growth and metastasis. The is not as efficient as oxidative phosphorylation (yielding rhythmic expression of the PER genes are reported to be only 2 mol of ATP/mole of glucose instead of 36 mol ATP/ altered in primary breast tumors (Chen et al. 2005) as well mole of glucose), it has certain benefits for tumor cells. as in breast cancer cell lines (Xiang et al. 2012). A recent Glycolysis results in more rapid production of ATP, fatty study demonstrated the association of the core clock gene acids and nucleotides that are needed by proliferating BMAL2 in ER breast cancer metastasis (Ha et al. 2016). tumor cells that need to double their biomass to divide. Furthermore, activation of REV-ERBA and REV-ERBB by a Furthermore, the generation of lactic acid promotes synthetic ligand is anti-proliferative in breast cancer cells. a tumor microenvironment that is protective against

© 2017SocietyforEndocrinology doan andothers Printed inGreatBritain The estrogen- All three ESRR isoforms were identified ascoactivating and themajorityofgenes intheglycolyticpathways. (Cai a complexwithMYCto co-regulate glycolyticgenes regulated byMYC.ESRRA was foundtoparticipatein and modulators ofmetabolicpathwayssuchasMYC, genes (Dufour et al.2007). regions of many shared target and bind to regulatory and thatESRRAESRRGreadilyformheterodimers of enzymes in the glycolytic pathways (Cai overexpression ofESRRGalsoleadstoincreasedexpression probably involvesmuchgreatercomplexity, giventhat metabolic reprogrammingbyERRsinbreastcancers the tricarboxylicacidcycle(Eichner et al. 2010).However, through regulation of genes that control phosphorylation al.2013),ESRRG is thought to sustain oxidative et (Cai of enzymesthatregulatetheglycolysispathway promotes aerobic glycolysis through the upregulation cancer cells (Deblois& Giguere 2013).Although ESRRA in the regulation of metabolic reprogramming of breast suggested thatESRRAandESRRGhaveoppositeroles of favorableoutcome(Ariazi is correlatedwithESR1andERBB4,whicharemarkers poor outcome(Thewes ESRRA isassociatedwithincreasedrecurrenceand 2002).Although outcomes(Ariazi et al. distinct survival Giguere 2011). of mitochondrialbiogenesisandfunction(Eichner& regionsof705genesinvolvedinallaspects regulatory Together, thethreeERRisoformsrecognizeproximal and metabolicgenenetworks(Dufour co-operate withPROX1andBMAL1toregulatecircadian 2004).Intheliver, ESRRAwasreportedto (Mootha et al. genesinmousemyoblastcells oxidative phosphorylation positive feedbacklooptoregulatetheexpressionofmany gamma coactivatoralphagene(PGC-1α)inadouble- with theperoxisomeproliferator-activatedreceptor- al.2007).ESRRAwasreportedtoco-operate et Dufour across themitochondrialmembrane(Alaynick et al. 2007, of energysubstrates,productionandtransportATP ESRRG co-operatetocontrolgenesinvolvedinuptake of metabolicgenenetworks.Intheheart,ESRRAand maintaining energyhomeostasisthroughtheregulation 2013). BothESRRAandESRRGhavedominantrolesin high energydemand(Giguere2008, regulators ofenergymetabolisminmultipletissueswith ESRRG/NR3B3) havebecomerecognizedasthemaster breast cancer Nuclear receptorsin Published byBioscientifica Ltd. ESRRs alsointeractwithoncogenesthatareknown In thebreast,ESRRAandESRRGareassociatedwith et al. 2013).HIFdirectlyactivatesglucose transporters ERBB2. Manygenesintheglycolyticpathwaysare

Downloaded fromBioscientifica.com at09/27/202109:55:09AM t al.2015), et t al.2002).Ithasbeen et 58 Deblois &Giguere ESRRG expression : 3 t al.2011). et t al. 2013) et 180 180 HIF via freeaccess PROOF ONLY

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factors of HIF and to enhance HIF-induced glycolytic and on the cell compartment in which PPARG is activated angiogenic gene expression in hypoxic condition (Ao et al. though, with activation in cancer cells resulting in growth 2008). ESRRA also regulates the expression of ERRB2 inhibition while activation in stromal cells results in (Deblois et al. 2010), which was reported to translocate growth enhancement of co-injected breast cancer cells to the mitochondria of tumor cells and regulate energy (Avena et al. 2013). Recent studies have also suggested an metabolism. Overexpression of mitochondrial ERBB2 involvement of PPARG and energy metabolism in breast decreases mitochondrial electron transport chain activity cancer. Firstly, several genes controlling the glycolytic and enhances cellular glycolysis (Ding et al. 2012). In pathways are found to have peroxisome proliferator addition, ERBB2 influences the glycolytic phenotype response element (PPRE) suggesting their regulation by through upregulation of lactate dehydrogenase (Zhao et al. PPARs (Sakharkar et al. 2013). Secondly, overexpression of 2009) as well as REV-ERBA, an NR that was reported to be PPARG in fibroblasts increased the production of l-lactate involved in glycolysis and fatty acid synthesis in breast and mitochondrial dysfunction. In addition, PPARG cancer cells (Kourtidis et al. 2010). induces the activation of HIF1A, a transcription factor In summary, the ERRs are prominent regulators that promotes glycolysis (Avena et al. 2013). of gene networks controlling glycolysis and oxidative phosphorylation in metabolic tissues. In the breast, Control of breast cancer migration and metastasis ESRRA expression is associated with poor outcome and appears to be involved in reprogramming the cell to Breast cancer metastasis accounts for the majority of favor aerobic glycolysis, a metabolic state characteristic of deaths from breast cancer. Early detection and a deeper cancer cells. ESRRG, on the other hand, is associated with understanding of the metastatic process are critical to better outcome and is involved in maintaining oxidative develop therapeutic interventions. Metastasis involves a phosphorylation, a metabolic state characteristic of complex cascade of steps starting with invasion by the normal cells. However, given that ESRRA and ESRRG can primary tumor of the surrounding host tissues, followed by form heterodimers and readily bind to many shared target intravasation and dissemination of the tumors cells via the genes, the complexity of the mechanisms for controlling blood or lymphatic system, infiltration and colonization their specificity of action is still to be deciphered. at the distant site. Several factors and pathways are known to influence cancer metastasis including disintegration Peroxisome proliferator-activated receptors of cell-to-cell adhesion, proteolytic remodeling of the (PPARs) PPARs function as heterodimers with the extracellular matrix, cell motility, evasion of immune and Journal of Molecular Endocrinology retinoid receptors (RXR) and regulate various genes that apoptotic signals and angiogenesis. Although substantial are involved in lipid metabolism and energy homeostasis. information is known about the process of metastasis, the Through these pathways, PPARs influence various molecular basis of breast cancer metastasis remains poorly cancer-related cellular processes such as proliferation, understood. NRs, being master regulators of almost every differentiation and survival (Michalik et al. 2004). Three physiological aspect of life, are likely to be intimately PPAR isotypes (PPARA/NR1C1, PPARD/NR1C2 and involved in the metastasis process. Here, we summarize PPARG/NR1C3) are known, each with unique expression the current understanding of the roles of various NRs in profile and functional roles. The PPARs showed decreased biological pathways affecting breast cancer metastasis. expression in breast cancer compared to normal breast (Muscat et al. 2013). The role of PPARD in breast cancer Estrogen receptors The estrogen receptors alpha tumorigenesis is unclear. Although activation of PPARD (ESR1) and beta (ESR2) appear to have distinct roles in has been shown to inhibit breast cancer cell line breast cancer progression and metastasis, with reports of tumorigenicity (Yao et al. 2014), inhibition of PPARD ESR1 signaling enhancing breast cancer cell migration and by inverse agonists was reported to inhibit breast cancer invasion, whereas ESR2 signaling has the opposite effects. cell invasion (Adhikary et al. 2013). PPARG is the best Emerging evidence suggests that estradiol’s positive studied of the 3 PPAR subtypes and has been reported effect on cell migration and invasion appears to be to have an anti-proliferative effect on breast cancer cells mediated through ESR1’s extranuclear signaling. ESR1 (Pon et al. 2015) and is associated with better outcomes extranuclear signaling is mediated through the PI3K, based on survival analysis of PPARG protein expression MAPK and c-Jun N-terminal kinase pathways (Li et al. level in BC tissue microarrays (Abduljabbar et al. 2015a). 2010, Zheng et al. 2011) with the involvement of PELP1 The downstream effect of PPARG seems to be dependent (Chakravarty et al. 2010), focal adhesion kinase (FAK)

adhesion kinase(FAK) (Graham offocal progestins alsoenhancethephosphorylation is increasedbyprogestins.Inaddition,progesterone/ 2013) suggestingamechanismthroughwhichmigration ( matrix metalloproteases(MMPs),β plasminogen activator (uPA), uPA receptor(uPAR), modulated theexpressionofgenessuchasurokinase activation ofMAPK,PI3K/AktandGTPase/RhoA that contributedtobreastcancermetastasis.Progestin that PGRactivatedcytoplasmicsignalingcascades Carnevale andcoworkers(Carnevale and metastasis.UsingaDNA-bindingmutantPGR, pathways isimplicatedinbreastcancermigration PGRA-predominant breast cancers. potentially contributingtothepooreroutcomesseenin migration andincreasedinvasion(McGowan al.2005),enhanced et adhesion signaling(Graham altered progestin response, including increased focal 2004). However, predominanceofPGRAresultsinan isoform levels,isinhibitedbyprogestins(McGowan of T-47D breastcancercells,expressingequivalentPGR and decreasedmigration(Lin and focalcontacts,consistentwithincreasedadhesion PGR, progestintreatmentincreasesactinstressfibers 2004, al. 2000, 2001, et invasiveness (Lin acting through nuclear PGR inhibit cell migration and PGR isoformandcontextdependent.Ingeneral,progestins and invasivepotential.However, theseeffectsareligand, progestin effectsonbreastcancercelladhesion,migration (Mote et al. 2015).Anumberofstudieshavedemonstrated with apoorerresponsetotheanti-estrogentamoxifen 2002)andisassociated in diseaseprogression(Mote et al. 1995).Thisdisruptionisseenearly PGRA) (Graham et al. cancer resulting in a predominance of one isoform (usually commonly theirexpressionbecomesderegulatedinbreast are equivalentlyexpressedinmostnormalcells,but al. 1990). PGRA and PGRB et a single gene (Kastner PGRB) arisingfromalternatepromoteractivitiesdriving expressed astwofunctionallydifferentforms(PGRAand Progesterone receptors ( and influencingbreastcancer progressionandmetastasis cytoskeletal reorganization involved incellularmotility formation andturnoverof focaladhesionpointsand predominance (Graham Bellance breast cancer Nuclear receptorsin Carnevale Luo &Guan2010). Published byBioscientifica Ltd. Crosstalk betweenPGRandcytoplasmicsignaling t al.2007).Incellstransfectedwith et Carnevale t al.2013),andthisisenhancedwithPGRA et t al.2007, et

Downloaded fromBioscientifica.com at09/27/202109:55:09AM t al.2008, et Fu t al.2005),promotingthe et 2000, et al. PGR inthehumanis et al. 2005, 1-integrin andPAI-1 et al. 2007)reported 58 t al. et McGowan : 3 2001). Invasion t al. et Bellance Fu 2004), et al. et al. 2008, 182 182 et al. via freeaccess

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Review t b doan and others Nuclear receptors in 58:3 183 breast cancer

PGR has also been reported to exert ligand- findings highlight that RARB is necessary for mediating the independent effects on breast cancer cell morphology anti-migratory effect of retinoic acid through modulation and migration (Jacobsen et al. 2005, Carnevale et al. 2007, of expression of genes involved in cell migration. Bellance et al. 2013). Un-liganded PGRA was shown to differentially regulate genes involved in cell adhesion Estrogen-related receptors Aside from their and increase adhesiveness and migration in inducible prominent role as master regulators of energy metabolism, cells expressing just one isoform (Jacobsen et al. 2005). the ERRs have been reported to influence the migratory However, in a recent study using bi-inducible MDA-MB-231 potential of breast cancer cells. Knockdown of ESRRA cells, un-liganded PGRB but not PGRA increased cell dramatically decreased the migratory potential of breast migration via differential effects on focal adhesion cancer cells (Stein et al. 2008), later determined to be signaling (Bellance et al. 2013). Furthermore, it has been mediated through VEGF (Stein et al. 2009) and WNT11 demonstrated that extensive ligand-independent action (Dwyer et al. 2010) signaling pathways, which are known of PGRB are dependent on specific post-translational regulators of angiogenesis. Inactivation of ESRRA also modifications, particularly phosphorylation, and resulted in impaired directional migration of breast cancer associated with pro-survival pathways (Daniel et al. 2007, cells, mediated through enhanced stability of RHOA, a Faivre et al. 2008, Knutson et al. 2012). These findings in protein involved in controlling oriented cellular migration the absence of ligand suggest that disrupted PGR isoform (Sailland et al. 2014). ESRRA itself was found to be a target expression may have particular importance in the context of miR-137 (Zhao et al. 2012). Therefore, consistent with of post-menopausal breast cancer, where circulating reports of its association with poor prognosis, activation progesterone is low or absent. of ESRRA has a pro-migratory effect on breast cancer cells. In summary, the emerging picture is that the effects By contrast, and consistent with its association with better of PGR and progesterone on breast cancer metastasis, breast cancer outcome, ESRRG was reported to promote adhesion and invasion are context dependent and mesenchymal-to-epithelial transition and decrease influenced by the relative ratio of PGR isoforms being breast cancer cell invasiveness through activation of expressed, the presence of ligands and whether PGR E-cadherin (Tiraby et al. 2011). Therefore, similar to their functions as a transcription factor or activator of signaling opposing roles in metabolic reprogramming, ESSRA and cascades, but that PGR contributes to increased invasive ESSRG display opposing influences on breast cancer cell and metastatic behavior in a number of contexts. migration and invasiveness. Journal of Molecular Endocrinology Retinoic acid receptors Several studies demonstrated NUR77 NUR77 (NR4A1) expression is elevated in both the anti-proliferative and anti-migratory effect of retinoids ER+ and ER− breast tumors (Muscat et al. 2013), and on breast cancer cells. Specifically, all-trans retinoid acid NUR77 expression is correlated with decreased relapse- (ATRA) was reported to modulate several migration-related free survival in breast cancer (Alexopoulou et al. 2010), proteins such as downregulation of MMP-1, MMP-2, consistent with reports of its pro-oncogenic role in breast cancer (Hedrick et al. 2015). Contradictory to a MMP-9, FAK, NF-κB and p-ERK and upregulation of E-cadherin in breast cancer cell lines (Liu et al. 2003, previous report of NUR77 having anti-migratory effects in Dutta et al. 2009, 2010). The anti-migratory effect of MCF-10A breast cancer cells, recently, NUR77 expression retinoids on breast cancer cells were shown to be was shown to have pro-migratory effects through activation mediated through RARB with treatment of RA or RARB of TGF-beta signaling (Zhou et al. 2014), which is known agonist resulting in significantly reduced cell migration to have an important role in breast cancer metastasis while treatment with RARA or RARG agonists did not (Moore et al. 2008, Kohn et al. 2012, Luwor et al. 2015). (Flamini et al. 2014). RARB is the only member of the RARs showing decreased expression in breast cancers COUP-TF1 and COUP-TF2 COUP-TFs are orphan (Muscat et al. 2013). RARB showed progressively decreased nuclear receptors primarily known for their important expression during breast carcinogenesis, with only roles in organogenesis including angiogenesis, cellular around 50% of invasive breast carcinoma expressing growth, differentiation and migration (Boudot et al. RARB (Xu et al. 1997). Transduction of RARB2 resulted 2011). Their roles in breast cancer growth and progression in significant reduction in metastasis rate in a mouse have recently been highlighted. Both COUP-TF1 and xenograft model (Treuting et al. 2002). Together, these COUP-TF2 expression are lower in breast tumors

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