for growth and proliferation. Testosterone, the main androgen, is primarily synthesized in the testes; others are synthesized in the adrenal gland and can be converted to testosterone in peripheral tissues. In some of the target cells, testosterone can be converted to its very potent metabolite dehydrotestosterone (DHT). Testosterone and DHT exert their function by binding to the androgen receptor to initiate the androgen signaling pathway. The receptor is a member of the nuclear receptor superfamily of ligand activated transcription factors. [To access the diagram for the normal androgen signaling pathway, click here].The affinity of the receptor for DHT is much higher than its affinity for testosterone. The irreversible conversion of testosterone into DHT is carried out by the steroid-5-alpha reductase (Srd5a). Of the two isoenzymes - Srd5a1 and Srd5a2, Srd5a2 has higher affinity for testosterone and is the one mostly expressed in the prostate. Interestingly, in prostatic cancer cells increased expression of isoenzyme 1 and decreased expression of isoenzyme 2 are observed. A widely used approach in the treatment of prostate cancer is the reduction/ablation of plasma testosterone levels medically or surgically. While the approach is initially beneficial, over time the malignant cells acquire androgen independence mostly due to the androgen independent activity of the receptor. The receptor has been reported to be amplified, and to acquire mutations that render it capable of binding other steroids, non-steroids and even antagonists or mutations that truncate the polyglutamine (CAG) repeat. The receptor is composed of several domains: the N-terminal regulatory domain containing CAG glycine repeats (NTD), the DNA binding (DBD), a hinge and the ligand binding (LBD) domains. The N-domain is the site of interaction with the many regulatory proteins that shape the transcriptional activity of the receptor. The length of CAGs ranges between 8 and 35 repeats. In prostate cancer, a decrease in the repeat length has been associated with the aggressiveness of the condition (in other conditions, an increase). Alterations in genes whose products modulate the receptor such as the Ncoa2 coactivator and Ncor2 corepressor along with alterations in chromatin regulatory elements have been observed. Gene fusion between androgen receptor-regulated genes and members of the ETS family of oncogenic transcription factors is a signature feature found in ~50% of cases. Fusion between the Tmprss2 gene and Erg members of the ETS family is a common and better documented case. The gene rearrangements have mostly been noticed in primary prostate cancer while the alterations/mutations associated with the androgen receptor are seen in the treatment-resistant, metastatic pancreatic tumors. To see the ontology report for annotations, GViewer and download, click here.
To link to the Cancer Disease Portal, click here or on the icon of the disease in the diagram.

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