Nuclear receptors and pathogenesis of pancreatic cancer

Table 1 Nomenclature of nuclear receptors

Subfamily official name (class)	NRNC group	Member trivial name	Official name	Abbreviation	Ligand
NR0 (domain-depleted receptors)	B [DAX-like receptors (DAX, SHP)]	Dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1	NR0B1	DAX-1	Orphan
NR1 (TR/RAR/PPAR/VDR-like receptors)	A (thyroid hormone receptors)	Short heterodimer partner	NR0B2	SHP	Orphan
		Thyroid hormone receptor α	NR1A1	TRα	GC-1, thyroid hormone
	B (retinoic acid receptors)	Thyroid hormone receptor β	NR1A2	TRβ	GC-1, thyroid hormone
		Retinoic acid receptor α	NR1B1	RARα	Am 580, all-trans-Retinoic acid, Arotinoid acid
		Retinoic acid receptor β	NR1B2	RARβ	Am 580, all-trans-Retinoic acid, Arotinoid acid
	C (peroxisome proliferator activated receptors)	Retinoic acid receptor γ	NR1B3	RARγ	Am 580, all-trans-Retinoic acid, Arotinoid acid
		Peroxisome proliferator-activated receptor α	NR1C1	PPARα	GW409544, GW7647, GW6471, Pirinixic acid, Palmitic acid, Leukotriene B4
		Peroxisome proliferator-activated receptor β	NR1C2	PPARβ/δ	Eicosapentaenoic acid, GW0742
		Peroxisome proliferator-activated Receptor γ	NR1C3	PPARγ	Rosiglitazone, GW1929, GW9662, GW409544, GW7647, 15-Deoxy-∆-12,14-prostaglandin, 15-Deoxy-∆-12,14-PGJ2
	D [Rev-Erb (NRD, E75)]F (RAR-related orphan receptors (ROR, HR3)	Rev-erbα	NR1D1	Rev-erbα	Orphan
			NR1D2	Rev-erbβ	Orphan
		Retinoic acid receptor-related orphan receptor α	NR1F1	RORα	Melatonin, CGP 52608
		Retinoic acid receptor-related orphan receptor β	NR1F2	RORβ	Melatonin, CGP 52608
		Retinoic acid receptor-related orphan receptor γ	NR1F3	RORγ	Melatonin,CGP52608
		Liver X receptor β	NR1H2	LXRβ	GW3969, T0901317, oxysterols
	H (ecdysone-like receptors)	Liver X receptor α	NR1H3	LXRα	GW3969, T0901317, oxysterols
		Farnesoid X receptor α	NR1H4	FXRα	GW4064, bile acid chenodeoxycholic acid
	I (vitamin D3-like receptors)	Vitamin D3 receptor	NR1I1	VDR	1,25-dihydroxyvitamin D3
		Pregnane X receptor	NR1I2	PXR	Hyperforin, SR12813, rifampicin, pregnenolone carbonitrile, T0901317, 24(S),25-epoxycholesterol, butamben
		Constitutive androstane receptor	NR1I3	CAR	Androstanol, CITCO, phenobarbital, ATE
NR2 (HNF4/RXR/TLL/COUP-like receptors)	A (hepatocyte nuclear factor 4)	Hepatocyte nuclear factor 4 α	NR2A1	HNF4α	Palmitoyl coenzyme A
		Hepatocyte nuclear factor 4 γ	NR2A2	HNF4γ	Orphan
	B (retinoid X receptors)	Retinoid x receptor α	NR2B1	RXRα	LGD 100268, GW0791, 9-retinoic acid
		Retinoid x receptor β	NR2B2	RXRβ	LGD 100268
		Retinoid x receptor γ	NR2B3	RXRγ	LGD 100268
		Testis receptor	NR2C1	TR2	Orphan
	E (tailless-like receptors)		NR2C2	TR4	Orphan
		Tailless	NR2E2	TLL	Orphan
		Photoreceptor-specific nuclear receptor	NR2E3	PNR	Orphan
	F [COUP-TF-like receptors (COUP-TF, SVP, EAR2)]	Chicken ovalbumin upstream promoter transcription factor IChicken ovalbumin upstream promoter transcription factor II	NR2F1	COUP-TFI	Orphan
			NR2F2	COUP-TFII	Orphan
		ErbA2-related gene-2	NR2F6	EAR2	Orphan
NR3 (ER/ERR/GR/MR/PR/AR)	A	Estrogen receptor	NR3A1	Erα	Fulvestrant, 17β-estradiol, 4-hydroxytamoxifen, Raloxifene
			NR3A2	Erβ	Fulvestrant, 17β-estradiol, 4-hydroxytamoxifen, Raloxifene
	B	Estrogen receptor-related receptor	NR3B1	ERRα	Orphan
			NR3B2	ERRβ	GSK4716, Diethylstilbestrol
			NR3B3	ERRγ	GSK4716, 4-hydroxytamoxifen
	C	Glucocorticoid receptor	NR3C1	GR	Dexamethasone, hydrocortisone, RU486
		Mineralocorticoid receptor	NR3C2	MR	Spironolactone, aldosterone, RU486
		Progesteron receptor	NR3C3	PR	R5020, progesterone, RU486
		Androgen receptor	NR3C4	AR	Dihydrotestosterone, RU486, Bicalutamide, R1881
NR4 (NGFIB-like receptors )	A [nerve growth factor IB-like receptors (NGFIB, NURR, NOR, HR38, CNR-8)]	Growth factor-inducible immediate early gene Nur77	NR4A1	Nur77	Orphan
		Nur-related protein 1	NR4A2	NURR1	Orphan
		Neuron-derived orphan receptor 1	NR4A3	NOR1	Orphan
NR5 (FTZ-F1/SF1-like receptors)	A [fushi tarazu F1-like receptors (SF1, FTF, FTZ-F1)]	Steroidogenic factor-1/ELP	NR5A1	SF1	Orphan
		Liver receptor homolog 1	NR5A2	LRH-1	Orphan
NR6 (GCNF)	A (germ cell nuclear factor)	Germ cell nuclear factor 1	NR6A1	GCNF1	Orphan

PPAR: Peroxisome proliferator-activated receptor; PDAC: Pancreatic ductal carcinoma; TZD: Thiazolidinediones; IFN: Interferon; RAR: Retinoic acid receptor; RXR: Retinoid X receptor; AR: Androgen receptor; ER: Estrogen receptor; LHR-1: Liver receptor homologue-1 receptor; COUP-TFII: Chicken ovalbumin upstream promoter transcription factor II.

Table 2 Expression of nuclear receptors and clinical trials

Nuclear receptor	Expression in primary PDAC	Clinical trials and results
PPAR (-α, -β, -γ)	PPARα: Unknown	None for PPARa and β/δ;
	PPARβ/δ: overexpressed; expression correlates with tumor stage, recurrence, and distant metastasis	PPARγ: TZD apparently reduce the risk of PDAC but PPARγ agonists do not improve survival
	PPARg: maybe overexpressed; expression correlates with shorter overall survival
RAR and RXR (-α, -β, -γ)	Yes (with the exception of RARb that is apparently lost during cancer development)	13-cis-RA in combination with IFN-γ: prolonged stable disease as well no improvement have been reported
AR	Yes	Phase II trials with the antagonist flutamide: increase in survival as well no effect have been reported
ER (-α, -β)	Yes	Tamoxifen with no benefit
NR4A1, NR4A2, NR4A3	NR4A1: overexpressed	None
	NR4A2 and NR4A3: unknown
LHR-1	Overexpressed	None
COUP-TFII	Overexpressed; expression correlates with shorter overall survival, tumor stage, and presence of metastasis	None

PPAR: Peroxisome proliferator-activated receptor; PDAC: Pancreatic ductal carcinoma; TZD: Thiazolidinediones; IFN: Interferon; RAR: Retinoic acid receptor; RXR: Retinoid X receptor; AR: Androgen receptor; ER: Estrogen receptor; LHR-1: Liver receptor homologue-1 receptor; COUP-TFII: Chicken ovalbumin upstream promoter transcription factor II.