Androgen Receptor

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 androgen receptor is most closely related to the progesterone receptor, and progestins in higher dosages can block the androgen receptor. The main function of the androgen receptor is as a DNA-binding transcription factor that regulates gene expression; however, the androgen receptor has other functions as well. Androgen regulated genes are critical for the development and maintenance of the male sexual phenotype.

1043446-39-4
CH5137291
1043446-39-4
PF 998425
1076225-27-8
B0084-457306
RAD140
1182367-47-0
1215085-92-9
GLPG0492
1215085-92-9
1215085-93-0
GLPG0492 R enantiomer
1215085-93-0
1240299-33-5
AZD-3514
1240299-33-5
B0084-474425
1242137-16-1
1297537-33-7
ORM-15341
1297537-33-7
B0084-470833
ODM-201
1297538-32-9
13311-84-7
Flutamide
13311-84-7
1539314-06-1
GSK-2881078
1539314-06-1
154992-24-2
RU 58841
154992-24-2
1628316-74-4
MI-136
1628316-74-4
Cl-4AS-1
188589-66-4
19608-29-8
19608-29-8

Background


The androgen receptor (AR) is a transcription factor belonging to the class I subgroup of the nuclear receptor superfamily, which includes other steroid, retinoid, and thyroid hormone receptors. These receptors regulate critical processes in organ development through transcriptional control. Members of this family are ligandresponsive and share structural and functional similarities with one another. Stimulated by androgens, the AR signaling pathway plays an important role in the development and differentiation of target tissues, as well as a critical role in the initiation, proliferation, and progression of prostate cancer to ablation-resistant disease.

The androgen receptor is a steroid hormone receptor that plays a central role in male sexual development as well as prostate cancer. Cloned and localized to chromosome Xq11-12 in 1988, the AR was found to have considerable structural and functional homology to the other steroid receptors, particularly the progesterone receptor (PR), mineralocorticoid receptor (MR), and the glucocorticoid receptor (GR). Steroid hormone receptors are ligand-activated transcription factors that are typically located in the cytosol and translocate to the nucleus upon activation. In the case of AR, circulating testosterone enters cells through passive diffusion and is immediately converted by 5α-reductase into Dihydrotestosterone (DHT). AR then binds to DHT in the cytoplasm causing dissociation from heat shock proteins, receptor phosphorylation, and dimerization. The AR translocates to the nucleus where it binds to androgen response elements in DNA, recruits co-activators, and activates the transcription of target genes that regulate growth and survival.

It is crucial to better understand the mechanisms that allow AR pathway reactivation to occur. Here will discuss the current knowledge in the field. There are several different known pathways of AR reactivation including increased production of ligand, increased AR levels, AR mutation, ligand independent activation through cross talk with kinase signaling pathways, and increased recruitment of co-activators.

AR mutation

AR mutation can allow AR pathway reactivation by permitting the receptor to respond to a broader range of ligands. Mutations of the AR gene are frequently found in clinical specimens of prostate cancer. Frequency of mutation ranges from 5% to 50% depending on the methodology used and type of tumor tissue analyzed. Generally, the frequency of mutation increases with the stage of the disease, being low in primary tumors and higher in metastatic tumors. Clinical data suggests that AR mutation is more important for tumor progression rather than tumor initiation. Treatment with androgen ablation therapy appears to provide a selective pressure for AR mutations that confer antagonist-agonist conversion ability. Mutations to the AR occur most frequently in the ligand-binding domain and can increase the sensitivity of the receptor as well as number of ligands that can activate the receptor.

Ligand-independent activation

Various growth factors can activate AR transcriptional activity in the absence of ligand. Insulin-like growth factor-1 (IGF-1), keratinocyte growth factor (KGF), and epidermal growth factor (EGF) all stimulate AR-mediated reporter gene transcription as well as PSA secretion in LNCaP cells in the absence of androgen. All of the aforementioned growth factors are ligands for receptor tyrosine kinases and activate complex kinase signaling cascades that ultimately lead to enhanced AR function. It is unclear whether this enhancement is due to direct interaction with AR or an alternate pathway. Moreover, whether this is truly "ligand-independent" activity is a source of debate as experiments were conducted using charcoal-stripped, androgen depleted serum which is known to still contain residual amounts of androgens. Notably, bicalutamide had the ability to block activation of AR by growth factors indicating that ligand binding remains important for growth factor stimulated AR activity.

Reference:

Kwon, Andrew Yong-Moon. The role of androgen receptor phosphorylation in hormone refractory prostate cancer growth. ProQuest, 2008.