Androgen receptor network in prostate cancer (WP2263)

Homo sapiens

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The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding either of the androgenic hormones, testosterone, or dihydrotestosterone in the cytoplasm and then translocating into the nucleus. The main function of the androgen receptor is as a DNA-binding transcription factor that regulates gene expression. The AR is important for therapeutic target in prostate cancer, thus many different inhibitors have been developed, primarily targeting the ligand binding domain of the protein, while inhibitors that target the N-terminal domain of the protein are still under development. Description source: [https://en.wikipedia.org/wiki/Androgen_receptor Wikipedia]

Authors

Phillip Febbo , Robertbaertsch , Daniela Digles , Egon Willighagen , Kristina Hanspers , Alex Pico , Martina Summer-Kutmon , Friederike Ehrhart , Lauren J. Dupuis , and Eric Weitz

Activity

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Organisms

Homo sapiens

Communities

CPTAC Diseases

Annotations

Disease Ontology

prostate cancer

Pathway Ontology

cancer pathway prostate cancer pathway

Participants
Query Drugst.One

Label Type Compact URI Comment
17-alpha-OH-Progesterone Metabolite hmdb:HMDB0000374
Dihydrotestosterone Metabolite hmdb:HMDB0002961
Androstenedione Metabolite cas:63-05-8
Progesterone Metabolite cas:57-83-0
Estradiol Metabolite cas:57-91-0
Testosterone Metabolite cas:58-22-0
Estrone Metabolite cas:53-16-7
Androstenediol Metabolite hmdb:HMDB0005849
dehydroepiandrosterone Metabolite cas:53-43-0
Pregnenolone Metabolite cas:145-13-1
17-alpha-OH-Pregnenolone Metabolite hmdb:HMDB0000363
Cholesterol Metabolite cas:57-88-5
SPINK1 GeneProduct ncbigene:6690 From Entrez Gene: The protein encoded by this gene is a trypsin inhibitor, which is secreted from pancreatic acinar cells into pancreatic juice. It is thought to function in the prevention of trypsin-catalyzed premature activation of zymogens within the pancreas and the pancreatic duct. Mutations in this gene are associated with hereditary pancreatitis and tropical calcific pancreatitis
Association with Prostate Cancer - Chinnaiyan Lab Cancer Cell Paper - ETS gene fusions have been characterized in a majority of prostate cancers; however, the key molecular alterations in ETS-negative cancers are unclear. Here we used an outlier meta-analysis (meta-COPA) to identify SPINK1 outlier expression exclusively in a subset of ETS rearrangement-negative cancers (∼10% of total cases). We validated the mutual exclusivity of SPINK1 expression and ETS fusion status, demonstrated that SPINK1 outlier expression can be detected noninvasively in urine, and observed that SPINK1 outlier expression is an independent predictor of biochemical recurrence after resection. We identified the aggressive 22RV1 cell line as a SPINK1 outlier expression model and demonstrate that SPINK1 knockdown in 22RV1 attenuates invasion, suggesting a functional role in ETS rearrangement-negative prostate cancers.
SPRY1 GeneProduct ncbigene:10252
AR GeneProduct ncbigene:367 AR
HSD3B2 GeneProduct ncbigene:3284
CYP17A1 GeneProduct ncbigene:1586
HSD3B1 GeneProduct ncbigene:3283
HSD17B7 GeneProduct ncbigene:51478
Hydroxyprogesterone aldolase GeneProduct eccode:4.1.2.30
F13B GeneProduct ncbigene:2165
HSD17B4 GeneProduct ncbigene:3295
Steroid-19-Hydroxylase GeneProduct ensembl:ENSG00000120054
HSD17B2 GeneProduct ncbigene:3294
HSD17B3 GeneProduct ncbigene:3293
HSD17B1 GeneProduct ncbigene:3292
p38 GeneProduct ensembl:ENSG00000112062
ATF1 GeneProduct ncbigene:466
ARID1A GeneProduct ncbigene:8289
PLK1 GeneProduct ensembl:ENSG00000166851
CDC25B GeneProduct ensembl:ENSG00000101224
CDC25A GeneProduct ensembl:ENSG00000164045
TMPRSS2 GeneProduct hgnc:7113
KLK3 GeneProduct ncbigene:354
KLK2 GeneProduct ncbigene:3817
NDRG1 GeneProduct ncbigene:10397
ABCC4 GeneProduct ncbigene:10257
ERG GeneProduct ncbigene:2078 Fusion partner with TMPRSS2 in about 40% of prostate cancers
ETV4 GeneProduct ncbigene:2118 Fusion partner with TMPRSS2 in about 40% of prostate cancers
ARID1B GeneProduct ncbigene:57492
SMARCA4 GeneProduct ncbigene:6597
SMARCC1 GeneProduct ncbigene:6599
SMARCC2 GeneProduct ncbigene:6601
SMARCD1 GeneProduct ncbigene:6602
SMARCD2 GeneProduct ncbigene:6603
SMARCD3 GeneProduct ncbigene:6604
ACTL6A GeneProduct ncbigene:86
ACTL6B GeneProduct ncbigene:51412
MAP2K1 GeneProduct ncbigene:5604
MAP4K1 GeneProduct ncbigene:11184
STAT3 GeneProduct ncbigene:6774
HGF GeneProduct ncbigene:3082
RAP1A GeneProduct ncbigene:5906
PTPN11 GeneProduct ncbigene:5781
PTEN GeneProduct ncbigene:5728
MAP2K2 GeneProduct ncbigene:5605
MAPK1 GeneProduct ncbigene:5594
CRKL GeneProduct ncbigene:1399
HRAS GeneProduct ncbigene:3265
FOS GeneProduct ncbigene:2353
DOCK1 GeneProduct ncbigene:1793 Interim Symbol: Dock1 predicted and Name: dedicator of cyto-kinesis 1 (predicted)
PXN GeneProduct ncbigene:5829
RAPGEF1 GeneProduct ncbigene:2889
RAF1 GeneProduct ncbigene:5894
SOS1 GeneProduct ncbigene:6654 Son of sevenless homolog 1 (Drosophila) (predicted)
Met GeneProduct ncbigene:24553
JUN GeneProduct ncbigene:3725
PTK2B GeneProduct ncbigene:2185
PIK3CA GeneProduct ncbigene:5290
PAK1 GeneProduct ncbigene:5058
ELK1 GeneProduct ncbigene:2002
MAPK8 GeneProduct ncbigene:5599
CRK GeneProduct ncbigene:1398
GAB1 GeneProduct ncbigene:2549
RAP1B GeneProduct ncbigene:5908
RASA1 GeneProduct ncbigene:5921
GRB2 GeneProduct ncbigene:2885
MAPK3 GeneProduct ncbigene:5595
MYC GeneProduct ncbigene:4609
EIF4EBP1 GeneProduct ncbigene:1978 From Entrez Gene: The protein encoded by this gene is a trypsin inhibitor, which is secreted from pancreatic acinar cells into pancreatic juice. It is thought to function in the prevention of trypsin-catalyzed premature activation of zymogens within the pancreas and the pancreatic duct. Mutations in this gene are associated with hereditary pancreatitis and tropical calcific pancreatitis
Association with Prostate Cancer - Chinnaiyan Lab Cancer Cell Paper - ETS gene fusions have been characterized in a majority of prostate cancers; however, the key molecular alterations in ETS-negative cancers are unclear. Here we used an outlier meta-analysis (meta-COPA) to identify SPINK1 outlier expression exclusively in a subset of ETS rearrangement-negative cancers (∼10% of total cases). We validated the mutual exclusivity of SPINK1 expression and ETS fusion status, demonstrated that SPINK1 outlier expression can be detected noninvasively in urine, and observed that SPINK1 outlier expression is an independent predictor of biochemical recurrence after resection. We identified the aggressive 22RV1 cell line as a SPINK1 outlier expression model and demonstrate that SPINK1 knockdown in 22RV1 attenuates invasion, suggesting a functional role in ETS rearrangement-negative prostate cancers.
SPRY2 GeneProduct ncbigene:10253
MYC Protein uniprot:P01106
FOXA1 Protein ncbigene:3169 DNA licensing factor for AR. Frequently occupies regions in enhancers with DNA recognition elements close to AR ARE
SPINK1 Protein uniprot:D6RIU5
FKBP5 Protein ncbigene:2289
TSC1 Protein uniprot:Q92574
AR Protein ncbigene:367 AR
RAD50 Protein uniprot:Q92878
MSH6 Protein uniprot:P52701
CDC2 Protein uniprot:P06493 Oncogene
BRCA1 Protein uniprot:P38398 Phosphorylated
CASP8 Protein uniprot:Q14790
ATR Protein uniprot:Q13535
BARD1 Protein uniprot:Q99728
CASP9 Protein uniprot:P55211
RB1 Protein uniprot:P06400
SMAD3 Protein uniprot:P84022
NOXA1 Protein uniprot:Q86UR1
BLM Protein uniprot:P54132
Q8NBS1 Protein uniprot:Q8NBS1
CDK4 Protein uniprot:P11802
MRE11 Protein uniprot:P49959
STAT1 Protein uniprot:P42224
BCL2 Protein uniprot:P10415
AKT1 Protein uniprot:P31749
CASP3 Protein uniprot:P42574
TP53 Protein uniprot:P04637
CHK2 Protein uniprot:O96017 Phosphrylated
JAK1 Protein uniprot:P23458
MSH2 Protein uniprot:P43246
BAX Protein uniprot:Q07812
PRKDC Protein uniprot:P78527
CHK1 Protein uniprot:O14757
BRCA1 Protein uniprot:P38398
MMP1 Protein uniprot:P03956
CDK2 Protein uniprot:P24941
BAD Protein uniprot:Q92934
ATM Protein uniprot:Q13315
SMAD2 Protein uniprot:Q15796 Tumor supressor
E2F1 Protein uniprot:Q01094
MDM2 Protein uniprot:Q00987 Oncogene
SP1 Protein ncbigene:6667 DNA licensing factor for AR. Frequently occupies regions in enhancers with DNA recognition elements close to AR ARE
TSC2 Protein uniprot:P49815
RHEB Protein uniprot:Q15382
MTOR Protein uniprot:P42345
RICTOR Protein ncbigene:253260
RPTOR Protein uniprot:Q8N122
4EBP1 Protein uniprot:Q13541
EIF4E1B Protein uniprot:A6NMX2
CCND1 Protein uniprot:P24385

References

  1. The role of SPINK1 in ETS rearrangement-negative prostate cancers. Tomlins SA, Rhodes DR, Yu J, Varambally S, Mehra R, Perner S, et al. Cancer Cell. 2008 Jun;13(6):519–28. PubMed Europe PMC Scholia
  2. MicroRNA-21 targets tumor suppressor genes ANP32A and SMARCA4. Schramedei K, Mörbt N, Pfeifer G, Läuter J, Rosolowski M, Tomm JM, et al. Oncogene. 2011 Jun 30;30(26):2975–85. PubMed Europe PMC Scholia
  3. MiR-21 induced angiogenesis through AKT and ERK activation and HIF-1α expression. Liu LZ, Li C, Chen Q, Jing Y, Carpenter R, Jiang Y, et al. PLoS One. 2011 Apr 22;6(4):e19139. PubMed Europe PMC Scholia