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Mol Endocrinol. 2014 Feb; 28(2): 157–172.

Published online 2013 Dec 2. doi: 10.1210/me.2013-1291

PMCID: PMC3896638

Minireview: Role Of Orphan Nuclear Receptors in Cancer and Potential as Drug Targets

Stephen Safe, Un-Ho Jin, Erik Hedrick, Alexandra Reeder , and Syng-Ook Lee

Department of Veterinary Physiology and Pharmacology (S.S., E.H., A.R.), Texas A&M University, College Station, Texas 77808; and Institute of Biosciences and Technology (S.S.,

U.-H.J., S.-O.L.), Texas A&M Health Science Center, Houston, Texas 77030

Corresponding author.

Address all correspondence and requests for reprints to: Stephen Safe, Department of Veterinary Physiology and Pharmacology, 4466 Texas A&M University, College Station, TX

77843-4466., E-mail: [email protected].

Received 2013 Sep 17; Accepted 2013 Nov 21.

Copyright © 2014 by The Endocrine Society

Abstract

The nuclear orphan receptors for which endogenous ligands have not been identified include nuclear receptor (NR)0B1 (adrenal hypoplasia

congenita critical region on chromosome X gene), NR0B2 (small heterodimer partner), NR1D1/2 (Rev-Erbα/β), NR2C1 (testicular receptor

2), NR2C2 (testicular receptor 4), NR2E1 (tailless), NR2E3 (photoreceptor-specific NR [PNR]), NR2F1 chicken ovalbumin upstream

promoter transcription factor 1 (COUP-TFI), NR2F2 (COUP-TFII), NR2F6 (v-erbA-related protein), NR4A1 (Nur77), NR4A2 (Nurr1),

NR4A3 (Nor1), and NR6A1 (GCNF). These receptors play essential roles in development, cellular homeostasis, and disease including cancer

where over- or underexpression of some receptors has prognostic significance for patient survival. Results of receptor knockdown or

overexpression in vivo and in cancer cell lines demonstrate that orphan receptors exhibit tumor-specific pro-oncogenic or tumor suppressor-like

activity. For example, COUP-TFII expression is both a positive (ovarian) and negative (prostate and breast) prognostic factor for cancer

patients; in contrast, the prognostic activity of adrenal hypoplasia congenita critical region on chromosome X gene for the same tumors is the

inverse of COUP-TFII. Functional studies show that Nur77 is tumor suppressor like in acute leukemia, whereas silencing Nur77 in pancreatic,

colon, lung, lymphoma, melanoma, cervical, ovarian, gastric, and some breast cancer cell lines induces one or more of several responses

including growth inhibition and decreased survival, migration, and invasion. Although endogenous ligands for the orphan receptors have not been

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identified, there is increasing evidence that different structural classes of compounds activate, inactivate, and directly bind several orphan

receptors. Thus, the screening and development of selective orphan receptor modulators will have important clinical applications as novel

mechanism-based agents for treating cancer patients overexpressing one or more orphan receptors and also for combined drug therapies.

The nuclear receptor (NR) superfamily of ligand-activated receptors exhibit a common modular structure (Figure 1A) and play essential roles,

not only in maintaining cellular homeostasis but also in various disease processes including cancer (1 – 5). The intricate interplay between the

activation or deactivation of NRs by different structural classes of endogenous ligands, such as the steroid and thyroid hormones, lipids, vitamins

and other biochemicals, is essential for their function. The 48 NR family members have been classified into subgroups based on the identification

of endogenous ligands for each receptor (1

). The endocrine receptors include the steroid hormone receptors that bind steroid hormones and the

heterodimeric receptors that partner with the retinoid X receptor and bind thyroid hormones, retinoids, and vitamin D. The identification of

specific endogenous ligands for the endocrine receptors has facilitated the design and development of selective receptor modulators (SRMs) that

exhibit tissue-specific agonist or antagonist activities (6) and are used extensively for treatment of hormone-/hormone receptor-dependent

diseases (7, 8). Tamoxifen is one of many selective estrogen receptor (ER) modulators used in endocrine therapies for treating ER-positive

breast cancer patients (9, 10).

The adopted orphan receptors are a second major subtype of NRs that are subdivided into 2 groups based, in part, on their ligands. The lipid

sensor receptor subtypes and their ligands include retinoid X receptor (9- cis-retinoic acid), peroxisome proliferator-activated receptors

(PPARs) (fatty acids), liver X receptor (oxysterols), farnesoid X receptor (bile acids), and pregnane X receptor, which binds cholesterol

derivatives. The enigmatic orphan receptor subtype includes constitutive androstane receptor (androstane and many drugs/xenobiotics),

hepatocyte nuclear factor-4, and steroidogenic factor-1/liver receptor homolog 1(LRH-1) (phospholipids), retinoid acid-related orphan

receptor (cholesterol and retinoic acids), and estrogen-related receptor (estrogens). Although adopted orphan receptors bind endogenous

ligands, it is not clear whether their functions in normal or diseased cells are regulated by these ligands. SRMs have been identified for many

adopted orphan receptors (11 – 14), and compounds such as the insulin-sensitizing thiazolidinediones (PPARγ agonists) have had extensive

clinical applications.

The orphan receptors are the third class of NRs, and endogenous ligands for these receptors have not been identified. The crystal structure of

the ligand-binding domain of the orphan receptor Nurr1 (NR4A2) shows that several hydrophobic residues protrude into the ligand-binding

pocket, and a typical coactivator-binding site is lacking (15), suggesting that some orphan receptors may not bind ligands (16, 17). Like other

NR classes, the orphan receptors play important roles in cellular homeostasis and diseases including cancer (18 – 24), and several recent reports

document the expression and potential functions of orphan receptors in different tumors and cancer cell lines (21 – 24). Breast tumors are

routinely classified as ER or ER , and expression of ER has prognostic significance that dictates selection of therapeutic regimens. However,+ −

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analysis of ER and ER tumors for expression (mRNA) of all 48 NRs also demonstrated the important prognostic significance of several

orphan receptors (21) (Figure 1B). The NR4A (Nur77/TR3, Nurr1, and Nor1) and NR2F6 [v-erbA-related protein (EAR2)] receptors are

uniquely overexpressed in all (ER and ER combined) tumors. Moreover, Nur77, EAR2, and chicken ovalbumin upstream promoter

transcription factor II (COUP-TFII) are among a limited group of NRs that are prognostic for breast cancer classification and histologic grade,

and COUP-TFII expression was a positive prognostic factor for tamoxifen-treated ER breast cancer patients (21

). Examination of lung tumor

and nontumor tissue indicated highly variable NR expression; however, gene combinations and individual receptors, such as the orphan receptor

small heterodimer partner (SHP, NR0B2), predicted enhanced survival for early-stage lung cancer patients (22). Moreover, expression of Nur77 in normal lung epithelium from patients was an indicator for good prognosis (23). NR profiling of the NCI60 cancer cell panel

demonstrated that relative expression levels of some orphan receptors also correlated with drug sensitivity (24). For example, cancer cell

sensitivity to microtubule-disrupting drugs was enhanced in cells expressing low levels of EAR2 and COUP-TFII, whereas high levels of the

orphan receptor tailless (TLX, NR2E1) correlated with sensitivity to 9-fluoroprednisolone (24).

It is clear that NRs are expressed in multiple cancers and contribute to the cancer cell phenotype, and ligands (agonists or antagonists) for these

receptors are important chemotherapeutic agents (7–10, 12–14, 19, 20). In this review, the prognostic and functional roles of orphan receptors

in cancer cells and tumors will be outlined, and the potential therapeutic applications of SRMs that target orphan receptors will be highlighted.

Expression And Prognostic Significance Of Orphan Receptors in Cancer

NR0B receptors

The NR0B orphan subfamily contains 2 unique receptors, namely dosage-sensitive sex reversal and adrenal hypoplasia congenita critical region

on chromosome X gene (DAX-1/NR0B1) and SHP/NR0B2. Both receptors express the ligand-binding domain (LBD) typical of all NRs, but

they do not contain a DNA-binding domain and therefore, their functions are dependent on receptor-protein, but not on receptor-DNA,

interactions (25 – 27). DAX-1 is expressed primarily in the hypothalamic-pituitary-adrenal/gonadal axis (28), and DAX-1 mutations result in

adrenal hypoplasia, hormone deficiencies, and gonadal dysfunction (hypogonadotropic hypogonadism) (29 – 31). Despite the limited expression

of DAX-1 in normal tissues, this receptor is more highly expressed in mammary (32, 33), endometrial (34), ovarian (35), adrenocortical, and

pituitary (36, 37), lung (38), and prostate (39) tumors, and Ewing's sarcoma (40 – 44). The prognostic significance of high or low expression of

DAX-1 has been reported only for a limited number of cancers. For example, in a cohort of node-negative breast cancer cases, low and high

DAX-1 mRNA expression correlated with poor and enhanced survival, respectively (33) (Figure 1B). DAX-1 was also highly expressed in

endometrial tumors compared with nontumor tissues and, although DAX-1 expression was inversely correlated with tumor grade, a correlation

between DAX-1 levels and disease-free survival was not observed (34

). Nuclear DAX-1 was also highly expressed in 21/40 prostate tumors,

and immunoreactivity for receptor expression was inversely correlated with Gleason score. In contrast, DAX-1 was expressed at a high

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frequency in epithelial ovarian tumors, and levels correlated with several tumor parameters (eg, size, grade, Ki-67 labeling) including decreased

disease-free survival (35) and, in lung cancer, DAX-1 expression was a negative prognostic factor associated with high rates of lymph node

metastasis and decreased disease-free survival (38). SHP (NR0B2) also lacks the conserved DNA binding domain common to other NRs, and

SHP is widely expressed in multiple tissues (45 – 47). Studies on the expression and prognostic significance of SHP in tumors are limited to

reports of higher receptor levels in hepatocellular carcinomas compared with normal liver (48 – 50) and higher levels in intestinal metaplasia (a

precancerous lesion) compared with gastric mucosa (51). Thus, the prognostic significance of high or low expression of DAX-1 and SHP is

variable and tumor specific (Figure 1B), and the underlying mechanisms that trigger altered expression of these genes in specific tumors has not been reported.

NRID receptors

Rev-erbα (NRID1) and Rev-erbβ (NRID2) are widely expressed in tissues (52) and play an integral role in regulation of circadian rhythms and

important mammalian molecular clock genes such as Bmal1 and Clock (53 – 55). Examination of more than 100 breast tumors showed Rev-erbα

was the only NR receptor among the 66 amplified genes that correlated with poor clinical outcomes (56). Rev-erbα, in combination with

SMARCE1/BIRC5 copy numbers, was a significant predictor of breast tumor recurrence (within 5 years) of women with ER/PR-positive or -

negative tumors (57); however, these results were in contrast to a recent study showing lower expression of Rev-erbα in breast tumors (ER

and ER ) than in normal breast tissue (21).

NR2C receptors

The orphan nuclear testicular receptor 2 (TR2; NR2C1) and TR4 (NR2C2) are structurally related and exhibit comparable expression patterns

in multiple tissues (58), and expression of both receptors are lower in ER and ER breast cancer compared with normal breast tissue (21).

However, their importance as prognostic factors for breast or other tumors has not been reported. A recent study reported that the testicular

orphan NR4-associated protein 16 (TRA16) was overexpressed in approximately 90% of non-small cell-lung tumors compared with

nondetectable levels in normal lung tissue and was a negative prognostic factor for patient survival (59). It was hypothesized that TRA16

interacts with TR2, resulting in derepression of ERβ, which plays an inhibitory role in lung tumorigenesis.

NR2E receptors

The nuclear orphan receptor TLX (NR4E1) has been extensively characterized in mouse models as an important neurogenesis gene required for

maintaining neural stem cells (59 – 64), and the expression and prognostic significance of TLX have been extensively investigated in brain cancers

(65 – 70). TLX is overexpressed in neurocytomas compared with expression in the ventricular zone and neuroendocrine-specific protein ( 65)

and in proliferative and mesenchymal-like subtypes of astrocytomas compared with the proneural subtype, and this is also observed for other

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neural stem cell markers. TLX is overexpressed in gliomas (67, 68); high levels of TLX mRNA in tumors correlated with decreased patient

survival (68), and TLX expression was higher in more aggressive (grades III and IV) compared with less aggressive (grade II) tumors (69) (

Figure 1B).

The photoreceptor-specific NR (PNR) (NR2E3) was identified in a search for TLX-related genes, and PNR expression is primarily observed in

the retina and retinal cells (71, 72). A woman with paraneoplastic retinopathy and poorly differentiated lung carcinoma expressed antibodies

against PNR (73), and serum PNR autoantibodies were higher in pancreatic cancer patients than in noncancer patients (74). There was also a

correlation between expression of ERα (ESR1) and PNR in the NCI-60 cancer cell lines and in breast tumors from 2 different patient cohorts

(75), and higher or lower expression of PNR correlated with good or poor clinical outcomes, respectively. Expression of PNR in breast tumors

was also associated with enhanced recurrence-free survival of breast cancer patients treated with tamoxifen (75) (Figure 1B). PNR protein was

also detected in ER-positive MCF-7 and T47D breast cancer cell lines, and knockdown of PNR significantly decreased ERα and estrogen-

induced cell proliferation and estrogen-responsive genes. Although the expression and prognostic significance of TLX and PNR in multiple

tumor types has not been extensively investigated, the prognostic significance of this subfamily of orphan receptors for decreased or enhanced

clinical outcomes should be further investigated in other tumor types.

NR2F receptors

The 2 chicken ovalbumin upstream promoter transcription factors (COUP-TFs) are COUP-TF1 (NR2F1) and COUP-TFII (NR4F2), which

are 97% and 99% homologous in their ligand- and DNA-binding domains, respectively, are widely expressed in multiple tissues and tumors

(76 – 78). Prostate tumor samples exhibited higher expression of COUP-TFII protein in tumor vs nontumor samples; approximately 60% of all

tumors exhibited intermediate to intense staining, whereas only 5% of the nontumor tissue stained positive for the receptor (79). Higher levels of

COUP-TFII expression predicted earlier recurrence of the disease. In another study, COUP-TFI was expressed in 21/28 prostate tumors;

however, correlations between expression levels and disease parameters were not observed (80). Among 119 breast tumors, 59% stained

positive for COUP-TFII, and higher expression of the receptor was a negative prognostic factor for several parameters including overall patient

survival (81). Another report showed that COUP-TFII was expressed in both breast tumor and nontumor tissue; COUP-TFII expression was

correlated with ERα expression, and high grade tumors tended to be COUP-TFII negative (82). Thus, at least for breast cancer, the prognostic

significance of COUP-TFII varies between studies, and this may be due to different subsets of patients. COUP-TFII is differentially expressed

in normal ovarian stroma (high) and epithelial (low) cells and in ovarian tumors, this expression pattern is reversed. Patients with tumors

expressing high epithelial/stroma ratios of COUP-TFII exhibited decreased tumor recurrence times (83). Another study reported relatively low

expression of COUP-TFII in ovarian tumors compared with nontumor tissue; however, COUP-TFII tissue compartmental ratios were not

reported (84). COUP-TFII was observed in more than 57% of tumors from colon cancer patients, and there was minimal expression in normal



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colonic mucosa; expression of the receptor correlated with increased rates of disease-free survival (85).

EAR2 (NR2F6) is the third and more distant member of the NR2F subfamily and is expressed in the human fetal liver and in mouse embryos

(86, 87). EAR2 is more highly expressed in both ER and ER breast tumors compared with normal breast tissue (88), and results of NR

profiling of the NCI-60 cancer cell panel show that cells with lower levels of EAR2 exhibit enhanced sensitivity to anticancer drugs targeting

microtubules (89). EAR2 is also more highly expressed in lymphomas (90) and colorectal tumors than in nontumor tissue. Among the nuclear

orphan receptors, NR2F subfamily members have been more extensively investigated for their expression and prognostic significance in multiple

tumors. Patients with tumors expressing high levels of COUP-TFII exhibited decreased (breast and prostate) and increased (colon and ovarian)

survival/decreased disease recurrence (Figure 1B) and, for breast and prostate cancer, the prognostic significance correlated with the pro-

oncogenic functions of COUP-TFII in mouse models (79, 91).

NR4A and NR6A receptors

NR4A receptors (NR4A1 [NGFI-B, Nur77, TR3]; NR4A2 [Nurr1]; NR4A [Nor1]) were initially identified as immediate-early genes induced

by nerve growth factors in PC12 cells, and these receptors are important in normal and tumor tissues (reviewed in References 92 and 93).

Expression of Nur77 in tumors and cancer cell lines has been extensively investigated, and higher levels are expressed in colon, pancreatic, lung,

and breast tumors compared with nontumor tissue (21, 94 – 96). Nur77 is highly expressed in both ER and ER breast tumors (21), and thereceptor tends to be more highly expressed in highly differentiated, lower grade tumors (97). Examination of publicly available array data for

lung tumors showed that high expression of Nur77 mRNA predicted increased patient survival (20), whereas in another cohort study, high levels

of Nur77 protein were prognostic for decreased patient survival (94) (Figure 1B). Nur77 expression was detected in whole bone marrow,

CD33 myeloid cells, and CD34 progenitors from healthy patients, whereas levels of Nur77 were decreased in acute myeloid leukemia

(AML) patients (98). Nur77 mRNA was also part of a gene signature in tumors associated with metastasis (99). Nurr1 is more highly

expressed in ER breast tumors compared with normal mammary tissue (21), and Nurr1 (cytosolic and nuclear) protein is more highly

expressed in bladder tumors compared with surrounding tissue (100). Higher levels of cytoplasmic Nurr1 were a prognostic factor for high

tumor grade, decreased survival, and increased distant metastasis in a cohort of bladder cancer patients (100). In breast cancer patients, Nurr1

expression was higher in normal breast epithelium than breast tumors, and expression of this receptor was inversely correlated with lymph node

metastasis but correlated with increased relapse-free survival (101) (Figure 1B). Nurr1 was more highly expressed in prostate tumors vs the

normal prostate and was correlated with tumor classification and Gleason score as a negative prognostic factor (102). Recent studies also show

that Nurr1 expression predicts poor survival and drug resistance in colon and gastric cancer patients (103, 104).

Nor1 is more highly expressed in ER and ER breast tumors compared with normal breast tissue; however, Nor1 levels did not correlate with

tumor characteristics (21). Expression of GCNF (NR6A1) is lower in both ER and ER breast tumors compared with normal mammary tissue

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(24), and cancer cells expressing low levels of GCNF exhibit higher sensitivity to the anticancer drug ecteinascidin (24).

Summary

Reports on prognostic significance and levels of nuclear orphan receptors in tumors are incomplete; however, Figure 1 illustrates that expression

of several orphan receptors in tumors predicts increased or decreased patient survival that is dependent on tumor type and, for some receptors,

their prognostic significance for a specific tumor varied between studies. Tumor suppressor genes and oncogenes are characteristically up- or

down-regulated (or mutated) in tumors; however, altered expression of other genes such as orphan receptors is not well understood.Examination of the ENCODE database (db = hg19 and c = chr12 and g = wgEncodeUwhistone) for DAX-1 in A549 lung cancer cells vs

normal human lung fibroblasts showed high expression of the H3K4me3 activation mark over the chromosome region of the DAX-1 gene only

in the cancer cell line. It is possible that overexpression of some orphan NRs in tumors (eg, lung) may be due to epigenetic effects and this is

currently being investigated.

Functions and Pathways Regulated by Orphan Receptors in Cancer

Multiple genes and their corresponding proteins serve as prognostic factors for selected tumors, and oncogenes such as Ras and Myc and

epidermal growth factor receptors that are activated or overexpressed in tumors also exhibit oncogenic functions. This section of the review will

outline the functions and pathways regulated by orphan NRs and determine correlations (or lack thereof) with their corresponding prognostic

significance. The functions of orphan receptors have primarily been investigated in knockout mouse models, by RNA interference (RNAi),

antisense constructs, or overexpression in cells; however, correlations between prognostic and functional (oncogenic or tumor suppressor-like)

activities of orphan receptors are limited.

NR0B receptors

DAX-1 expression is a negative (lung and ovarian) and positive (prostate and breast) prognostic factor for patient survival, and DAX-1 silencing

in lung cancer cells decreases growth, survival, and invasion, demonstrating pro-oncogenic functions for this receptor. DAX-1 and the

oncogenic fusion protein EWS (Ewing sarcoma)/FLI1 coordinately regulate multiple genes in Ewing' sarcoma, and EWS/FLI1 regulates DAX-1

expression in these tumors (40 – 44). In mouse embryonic stem cells, DAX-1 and LRH-1 (NR4A2) cooperatively mediate the activation of the

stem cell marker Oct4, and DAX-1/LRH-1 may play a role in stem cell and cancer stem cell function ( 105). DAX-1 interactions with EWS-

FLI1 and other NRs is both dependent and independent of the LXXLL motif that facilitates interactions with some receptors ( 106 – 114), and

this may competitively displace NR coactivators and other nuclear LXXLL-interacting nuclear factors. Although SHP expression varies in some

tumors, the correlation with patient outcomes has not been determined; however, SHP mice develop hepatocellular tumors at 12–15 months

of age, suggesting a possible tumor-suppressive function for this receptor in liver carcinogenesis, and this has been related to the inverse

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expression of SHP and cyclin D1 (48). SHP expression is higher in intestinal metaplasia than in gastritis mucosa, and SHP plays a tumor-

promoting role in this precancerous adenocarcinomal lesion by regulating expression of caudal-related homeobox gene (CDX1) that is involved

in intestinal metaplasia (51).

There is extensive literature on the mechanism of action of SHP in cancer and noncancer cell context, and a major function of this receptor

involves direct interactions with NRs, other transcription factors, and nuclear cofactors to inhibit gene expression. SHP interacts with 23 NRs,

17 nuclear cofactors including coactivators and corepressors, and 12 transcription factors including oncogenes (c-jun/JunD), tumor suppressors

(p53), and other factors such as NFκB that play a role in tumorigenesis (47, 115). Many SHP-interacting proteins have been identified instudies on the role of SHP in a noncancer cell context, and these interactions may also influence the tumorigenicity of transformed cell lines. SHP

expression is lower in prostate cancer cells compared with human prostate RWPE-1 epithelial cells and inversely correlated with miR-141 levels

that repress SHP (116). Overexpression of p53 in 293T cells enhanced proteasome-dependent degradation of SHP protein, and SHP

overexpression enhanced the ubiquitin ligase activity of MDM2 which, in turn, decreased p53 stability (117). Nur77 also binds and inactivates

p53, and Nur77 antagonists activate p53 and inhibit mammalian target of rapamycin (mTOR) signaling in lung cancer cells (94, 118), suggesting

that SHP ligands could also potentially affect p53 function. SHP also interacts with and inhibits ERα- and ERβ-mediated transactivation;

however, it is unclear whether these effects modify mammary carcinogenesis (119, 120). Thus, among the NR0B receptors, DAX-1 expression

is a prognostic factor for decreased lung cancer survival and exhibits pro-oncogenic activity (Figure 2); more extensive studies are required todefine the role of DAX-1 and SHP in tumorigenesis.

NRID and NR2C receptors

The function of Rev-erbα/β receptors in tumors and cell lines has not been determined; however, these receptors activate or repress multiple

genes including N-myc and deleted in breast cancer 1 (DBC1) through either direct DNA (promoter) binding or protein-protein interactions

(52, 121 – 126). Increased expression of TR4 was observed in prostate cancer stem/progenitor cells expressing CD133 (PCaCD133 )

compared with PCaCD133 cells, and knockdown of TR4 in PCaCD133 cells resulted in increased sensitivity to treatment with docetaxel

and etoposide, suggesting a role for TR4 in chemoresistance (127). TR2 and TR4 suppress ER-mediated gene expression and proliferation of

breast cancer cells (128, 129) and also suppress androgen receptor function in prostate cancer cell lines (130), due to direct interactions

between TR2/TR4 with other NRs or nuclear factors and with cis-promoter elements (59, 128 – 136).

NR2E receptors

TLX is highly expressed in brain tumors and is a prognostic factor for decreased patient survival (68), and in vitro and in vivo studies

demonstrate oncogenic-like activity of this receptor. Knockout of TLX in mouse models confirmed the role of TLX in promoting brain tumor

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formation and neural stem cell-dependent tumors (69). Silencing TLX in IMR-32 and SH-SY5Y neuroblastoma cells decreased cell growth and

anchorage-independent colony formation (70). Overexpression of TLX increased cell proliferation and foci formation in Ink4a/Arf

astrocytes, and tumorigenesis was also enhanced in mice bearing these astrocytes as xenografts (68). TLX overexpression resulted in

development of gliomas and glioma-like lesions in mice (67) and, in U87MG glioma cells, TLX overexpression increased cell proliferation and

formation of colonies in soft agar (68). The mechanisms of TLX-mediated pro-oncogenic activity are complex and may be linked to direct and

indirect regulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-2α through binding to von Hippel-Lindau protein

(70) and activation of cyclin D1 (68).

Knockout of PNR in ER-positive breast cancer cell lines decreased ERα-mediated responses including gene expression (75), and mechanistic

studies show that PNR in combination with protein inhibitor of signal transducer and activator of transcription (STAT)3 (protein inhibitor of

activated STAT 3), bind directly to the ERα gene promoter to regulate ERα gene expression (75). High-throughput genetic screens showed that

PNR induced apoptosis and p53-responsive genes, and this was due to stabilization of p53 by interactions with PNR and p300-dependent

acetylation of p53 (137). Regulation of ERα and p53 by PNR in cancer cells suggests the potential clinical importance of this gene as a drug

target.

NR2F receptors

The functions of COUP-TFII in tumor development have been investigated in mouse models with tissue-specific loss of COUP-TFII. For

example, in tumor xenograft and mouse mammary tumor models, the loss of COUP-TFII resulted in decreased tumorigenesis due to decreased

neoangiogenesis, and decreased tumor growth and metastasis were observed in the mammary tumor model (91). COUP-TFII knockdown (81)

or overexpression (138) in breast cancer cells confirmed a role for this receptor in breast cancer cell growth, survival, motility, and invasion

(138). These functional observations correlated with the prognosis of decreased survival of patients with tumors expressing high levels of

COUP-TFII (81). In contrast, the effects of COUP-TFII on drug resistance in breast cancer cells were dependent on the specific agent and cell

line (138, 139). For example, overexpression of COUP-TFII in triple-negative MDA-MB-231 cells enhanced the growth-inhibitory effects of

tamoxifen (139), whereas cells expressing low levels of COUP-TFII exhibited increased sensitivity to microtubule disrupting drugs such as taxol

(101). The loss of COUP-TFII in RIP-Tag2 mice resulted in inhibition of pancreatic islet tumorigenesis at multiple stages (140); however,

studies in pancreatic cancer cell lines have not been reported. In transgenic models of prostate cancer, loss of COUP-TFII decreased prostate

tumor progression and survival (79). The pro-oncogenic activity of COUP-TFII was further confirmed by overexpression of this receptor in

wild-type or transgenic mice with decreased or loss of phosphatase and tensin analog expression. COUP-TFII overexpression alone did not

initiate prostate tumorigenesis but clearly enhanced this process in mice with loss of phosphatase and tensin analog, thus confirming the tumor

promoter-like activity of COUP-TFII in prostate cancer (79). Low levels of COUP-TFII were observed in prostate cancer cell lines, and

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overexpression of the receptor inhibited androgen-induced cell growth and gene expression (141); these results were in contrast to the in vivo

studies. Overexpression of COUP-TFII in noninvasive A549 lung cancer cells increased invasiveness, and knockdown of the receptor in A460

cells that express relatively high levels of the receptor decreased invasiveness (142). These functional studies were consistent with pro-

oncogenic activity for COUP-TFII for breast, pancreatic, prostate, and lung cancer, whereas in ovarian cancer cells (ES-2 and TOV112D),

knockdown of COUP-TFII increased proliferation of ES2 cells but increased apoptosis in both cell lines (83).

COUP-TFII modulates gene expression through direct promoter DNA binding or through protein-protein interactions, and many of the genes

regulated by COUP-TFII, including angiopoietin-1 (91) and VEGF/VEGFR2 (81, 140), are associated with angiogenic pathways. COUP-TFIIalso interacts with nucleolin in breast cancer, and nucleolin coactivates COUP-TF-mediated regulation of retinoic acid receptor β in breast

cancer cells (82). COUP-TFII also modulates ligand-activated ERα signaling in breast cancer (139) and decreases androgen-dependent

activation of prostate-specific antigen in prostate cancer cells through direct COUP-TFII-AR interactions (141). COUP-TFII overexpression in

lung cancer cells enhanced invasiveness, and this was accompanied by activation of focal adhesion kinase, matrix metalloproteinase 2 and

urokinase receptor (142). COUP-TFII also regulates expression of several genes and pathways in ovarian cancer cells but not angiogenic genes

(83), indicating the importance of cancer cell context on the role of this orphan receptor. Knockdown of EAR2 by RNAi induces apoptosis in

colon cancer, and this is correlated with decreased expression of the antiapoptotic factor X-linked inhibitor of apoptosis (143). Loss of EAR2 in

RKO cells also decreases tumor growth in athymic mice bearing these cells as xenografts compared with growth of cells expressing wild-typeEAR2.

NR4A and NR6A receptors

Although Nur77 appears to be a tumor suppressor in the Nur77 /Nor1 mouse that spontaneously develops leukemia, knockdown or

overexpression studies in most cancer cell lines indicate that Nur77 is pro-oncogenic. Silencing of Nur77 in pancreatic, colon, lung, lymphoma,

melanoma, cervical, ovarian, and gastric cancer cell lines inhibited cell growth, survival, migration, and/or invasion (94, 99, 144 – 149).

Combined knockdown of histone deacetylase inhibitor-induced Nur77 and Nor1 increased growth and decreased apoptosis in AML cell lines

(150), whereas in other leukemia cell lines (eg, Jurkat), we have observed pro-oncogenic activity for Nur77 (our unpublished observations), and

studies on the tumor type-specific role of Nur77 in leukemic cells are ongoing. The oncogenic and tumor suppressor-like functions of Nur77 in

lung and AML cell lines and knockout mouse models, respectively, correlated with the decreased and increased survival of lung and AML

cancer patients expressing high levels of this receptor.

The caged retinoid compound CD437, and several analogs inhibit growth and induce apoptosis in lung and other cancer cell lines (151 – 161),

and these responses have been linked to Nur77 (162). Retinoid-induced proapoptotic responses are Nur77 dependent and are blocked by the

nuclear export inhibitor leptomycin B, indicating that the effects of CD437 and other apoptosis inducers are due to the extranuclear effects of

−/− −/−


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Nur77 (163). The mechanisms of extranuclear Nur77-mediated apoptosis in some cell lines involves a novel pathway in which Nur77 is

associated with mitochondria and forms a novel Nur77-bcl2 proapoptotic complex that induces release of cytochrome c and activation of the

intrinsic apoptosis pathway (163, 164). A peptide mimic of Nur77 that binds bcl2 and paclitaxel, which acts as a Nur77 mimic, also induce

apoptosis in cancer cells (165, 166). Platinum-resistant ovarian cancer cells have been linked to low Nur77 expression because platinum-

induced apoptosis is also due to nuclear export of Nur77 (167). The increased survival of liver cancer cells is due to expression of

chromodomain helicase/adenosine triphosphatase (ATPase) DNA-binding protein 1-like (CHD1L), which inhibits nuclear export of Nur77

(168). CD437 also induces nuclear translocation of SHP to form a complex with bcl-2; however, SHP, but not Nur77, binds CD437 and

structurally related analogs (169).

RNAi studies in cancer cell lines showed that Nurr1 was associated with bladder cancer cell invasion (170), melanoma cell migration (145),

prostate cancer cell growth, migration and invasion (102), and breast cancer growth (101). Nurr1 is also associated with drug resistance in

colon and gastric cancer cells (104). In contrast, it was also reported that gastrin induced Nurr1 expression in gastric cancer cells, and

knockdown or overexpression of the receptor showed that Nurr1 suppressed gastrin-induced migration and invasion of gastric cancer cells

(171). The differences between the 2 studies in gastric cancer cells may be due to gastrin-induced changes in intracellular cytosol-nuclear

shuttling of Nurr1, which favors cytosolic accumulation of the receptor (171). Thus, like Nur77, Nurr1 primarily exhibits oncogenic activity in

cancer cells and the decreased survival of bladder, gastric, and prostate cancer patients that overexpress Nurr1 correlates with the oncogenicactivity of this receptor in their corresponding cancer cell lines.

Combined knockdown of Nur77 and Nor1 in mice results in the rapid formation of AML in mice (98); however, the expression and role of

Nurr1 and GCNF in tumors is poorly defined and requires additional research. Although functional and prognostic studies on orphan receptors

in different tumor types are limited, with the exception of leukemia, overexpression of these receptors in solid tumors predicted decreased

survival, and this correlated with their oncogenic activities observed in corresponding cancer cell lines (Figure 2).

Orphan NR Ligands

The expression and pro-oncogenic or tumor suppressor-like functions of orphan receptors in tumors indicate that orphan receptor ligands actingas agonists or antagonists represent a potentially novel class of selective receptor modulators for cancer chemotherapy. Identification of ligands

for TLX, EAR2, and GCNF has not been reported; however, ligand binding and/or ligand-dependent activation or inactivation of the remaining

orphan NRs has been observed (Figure 3) and provides a basis for development of selected receptor modulators of orphan receptors.

NR0B receptors

The DAX-1 promoter has been used in a screening assay of 50 000 compounds in EWS/FLI1 in Ewing's sarcoma cells (172), and mithramycin



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was identified as the most effective agent. Mithramycin exhibits anticancer activity; however, inhibition of EWS/FLI1-mediated transactivation

by mithramycin could also be due to other activities of this drug, which inhibits transactivation of GC-rich gene promoter sites (173 – 176).

The adamantyl retinoid CD437 and related derivatives induce apoptosis in several cancer cell lines (151 – 157), and this compound specifically

binds SHP in a competitive displacement assay (Figure 2) (158 – 161). CD437 and other adamantyl retinoids and hepatocyte nuclear factor 4α

induce SHP in liver and liver cancer cells, and the receptor is equilibrated in nuclear, cytosolic, and mitochondrial fractions of the cell (169).

SHP also colocalizes with bcl-2 in the outer mitochondrial membrane, resulting in release of cytochrome c and induction of apoptosis. The

retinoid-induced nuclear translocation of SHP to mitochondria has also been reported for Nur77 (NR4A1), which also interacts with bcl-2(162) but does not bind CD437. The parallel functions of the adamantyl retinoids in inducing nuclear export of both SHP and Nur77 may also

be complicated by the reported SHP-mediated repression of nuclear Nur77 (177). Although it is clear that the adamantyl retinoids effectively

induce apoptosis in several different cancer cell lines, the interplay between SHP and Nur77 and their separate and combined roles in mediating

apoptosis in cancer cells has not been resolved.

NRID, NR2C, NR2E, and NR2F receptors

Heme associates with the LBD of Rev-erbα/β receptors (Figure 3) and enhances recruitment of the corepressor, nuclear receptor corepressor,

to repress target genes such as Bmal1 (178, 179). Synthetic Rev-erbα/β agonists and antagonists have been characterized and shown to befunctional (180 – 182), suggesting that these receptors may be druggable targets for specific tumors. The crystal structure of the LBD of TR4

shows that, like COUP-TFII, the ligand-binding cavity and the coactivator-binding sites on the AF-2 helix are blocked (183). Nevertheless,

TR4-dependent transactivation is enhanced by some coactivators, and both retinol and all-trans-retinoic acid bind the receptor (LBD) (183) (

Figure 3). PNR agonists have also been identified in transactivation assays (137, 184); however, the direct binding or effects of these

compounds have not been reported.

The crystal structure of the COUP-TFII LBD shows that the receptor exists in an autorepressed condition with helix α 10 extending into the

ligand-binding pocket, and the AF2 helix is folded into a position that blocks coactivator binding (88). Despite these constraints, 9-cis- and all-

trans retinoic acid induce COUP-TFII-dependent transactivation and enhance coactivator binding (Figure 3). These results suggest thatCOUP-TFII may also be targeted by tissue-selective agonists or antagonists that can be developed as anticancer agents to either activate or

inhibit the function of this receptor.

NR4A receptors

At least 2 structurally different classes of ligands that activate nuclear Nur77 have been reported, and these include cytosporone B (CsnB) and

related analogs (185, 186) and a series of 1,1-bis(3′-indolyl)-1-( p-substituted phenyl)methanes (C-DIMs) (95, 96, 117, 187 – 189) (Figure 3).

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896638/figure/F3/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896638/figure/F3/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896638/figure/F3/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896638/figure/F3/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896638/figure/F2/


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CsnB and related compounds directly bind Nur77, activate the receptor in transactivation assays, and induce recruitment of coactivators;

however, the proapoptotic activity of CsnB is due to both nuclear and extranuclear pathways. CsnB induces nuclear export of Nur77 to the

mitochondria, and CsnB also decreases expression of the antiapoptotic gene brain and reproductive organ-expressed (BRE) via nuclear Nur77-

dependent repression (185, 186). The C-DIM compounds are synthetic analogs derived from 1,1-bis(3′-indolyl)methane (DIM) which is a

major metabolite of indole-3-carbinol, a cancer chemopreventive and chemotherapeutic phytochemical that is one of the active components of

cruciferous vegetables. C-DIMs contain a substituted phenyl (or other aromatic) group and may also have indole ring substituents (Figure 3). A

subset of C-DIMs activate PPARγ in cancer cell lines (190, 191), and the p-methoxyphenyl analog (DIM-C-pPhOCH ) activates nuclear

Nur77-dependent transactivation in multiple cancer cell lines and, like CsnB, DIM-C-pPhOCH induces apoptosis and inhibits cancer cell and

tumor growth (94, 96). In addition, the p-hydroxyphenyl (DIM-C-pPhOH), p-carboxymethylphenyl (DIM-C-pPhCOOMe), and other analogs

have been identified as inactivators of Nur77 that also induce apoptosis and inhibit cancer cell and tumor growth ( 192). Studies on the direct

binding of C-DIMs to Nur77 are currently underway; however, using a combination of Nur77 silencing (siNur77) and treatment with DIM-C-

pPhOH, several Nur77-dependent genes/pathways associated with this receptor have been identified (94, 96, 192, 193). Nur77 activates

survivin and bcl2 through interaction of Nur77 with p300 and the DNA-bound Sp1 transcription factor, and siNur77 or DIM-C-pPhOH

decreases survivin and bcl2 expression in cancer cells (96). A second pathway is only observed in p53-positive cancer cell lines in which Nur77

binds and inactivates p53, and this has been linked to activation of mTOR signaling (94). Treatment of cancer cells with siNur77 or DIM-C-

pPhOH results in mTOR inhibition, and this is due to activation of p53 and p53-dependent induction of sestrin 2 which, in turn, activates themTOR inhibitor phospho-cAMP activated protein kinase-α (94). A third recently discovered pathway involves the regulation of the thioredoxin

genes that maintain low oxidative stress levels in pancreatic cancer cells, and transfection with siNur77 or treatment with DIM-C-pPhOH

induced oxidative and endoplasmic reticulum stress and apoptosis (193). These results not only demonstrate the effectiveness of agents that act

as Nur77 antagonists but also reveal the pro-oncogenic pathways regulated by Nur77 and the importance of the receptor as a drug target.

X-ray crystallographic studies of the LBD of Nurr1 showed that hydrophobic substituents fill the ligand-binding pocket, suggesting this may be a

true orphan receptor devoid of endogenous or exogenous ligands (15). A library screen for Nurr1 activators identified only 6-mercaptopurine

and a few structural analogs (Figure 3) that activated Nurr1 through the N-terminal and not the C-terminal LBD (194). However, substituted

benzimidazole and pyridinone derivatives and C-DIMs have subsequently been identified as potential Nurr1 agonists (195, 196), and the p-

chlorophenyl C-DIM analog (DIM-C-pPhCl) activates Nurr1 and is a potent inhibitor of bladder cancer cell and tumor growth (170). Nurr1 is

a potential target for cancer chemotherapy; however, more extensive characterization of Nurr1 agonists and antagonists and their receptor

binding is essential. Nor1 expression and function in tumors has not been reported; however, like Nurr1, 6-mercaptopurine induced Nor1-

dependent transactivation and prostaglandin A2-activated Nor1 via the LBD (197, 198) (Figure 3).

Summary and Conclusions

33

7/3/2016 Mi i i R l Of O h N l R t i C d P t ti l D T t

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Figure 1 illustrates the tumor site-specific expression and prognostic significance of orphan receptors. The prognostic significance of one or more

orphan receptors has been reported in multiple tumors, and orphan receptors such as TLX may be highly specific for brain tumors in which this

receptor is a negative prognostic factor and functions as an oncogene (67 – 69). Other orphan receptors such as DAX-1, COUP-TFII, and

Nur77 play a significant prognostic and/or functional role in multiple tumors (Figure 1B); however, for many tumors only one of the prognostic

or functional parameters is known. Reports for some receptors are contradictory, and the prognostic and functional parameters for many orphan

receptors vary with tumor type. For example, in most cancer cells and tumors, Nur77 exhibits pro-oncogenic activity, whereas Nur77

/Nor1 double-knockout mice rapidly develop AML-like leukemia and Nur77 may act as a tumor suppressor (98). The prognostic activity

of some receptors such as COUP-TFII and DAX-1 are also highly variable. High levels of DAX-1 expression are both favorable (breast,

prostate) and unfavorable (lung, ovarian), whereas COUP-TFII expression is a favorable (ovarian, colon) and an unfavorable (breast, prostate)

prognostic factor for a different set of cancer patients. Orphan NR expression in multiple cancers needs to be further investigated for its

prognostic significance and function and as a potential target for SRMs that can be used alone or in combination therapies.

Nur77 is among the most thoroughly investigated of the orphan NRs, and the prognostic and functional activity of this receptor is cancer cell and

tumor context dependent and is also influenced by ligand-induced nuclear and extranuclear (nongenomic) pathways as illustrated in Figure 4.

The extranuclear function of Nur77 is somewhat unique, and the nuclear-cytosolic ratios influence cell death and survival pathways as well as

drug efficacy. The CHD1L gene product inhibits nuclear export of Nur77 and Nur77-mediated apoptosis in liver cancer cells ( 168), and a

recent report suggests that cisplatin-induced apoptosis in ovarian cancer cells is dependent on nuclear export of this orphan receptor (167). The

antineoplastic activity of Nur77 is associated with ligand-activated genomic and nongenomic pathways, and it is possible that these dual

pathways may also be important for other orphan NRs. The expression of orphan receptors in tumors coupled with the ongoing identification of

receptor agonists and antagonists (Figure 3) indicate that selective orphan receptor modulators represent a novel and important class of

mechanism-based drugs that will have significant future clinical applications for cancer chemotherapy.

Acknowledgments

This work was supported by National Institutes of Health Grants (R01CA142697 and CA-124998), Texas AgriLife Research, and the Syd

Kyle Chair.

Disclosure Summary: The authors have nothing to disclose.

Footnotes

Abbreviations:

AML acute myeloid leukemia

−/

− −/−


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COUP-TF chicken ovalbumin upstream promoter transcription factor

CsnB cytosporone B

DAX-1 adrenal hypoplasia congenita critical region on chromosome X gene

DIM 1,1-bis(3′-indolyl)methane

EAR2 v-erbA-related protein

ER estrogen receptor

EWS Ewing sarcoma

LBD ligand-binding domain

LRH-1 liver receptor homolog 1

mTOR mammalian target of rapamycin

NR nuclear receptor

PNR photoreceptor-specific NR

PPAR peroxisome proliferator-activated receptor

RNAi RNA interference

SHP small heterodimeric partner

SRM selective receptor modulator

TR testicular receptor

VEGF vascular endothelial growth factor.

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