Molecular Biology of the Androgen Receptor

Androgen receptor (AR) is a member of the steroid hormone receptor family of molecules. AR primarily is responsible for mediating the physiologic effects of androgens by binding to specific DNA sequences that influence transcription of androgen-responsive genes. The three-dimensional structure of the AR ligand-binding domain has shown it is similar to other steroid hormone receptors and that ligand binding alters the protein conformation to allow binding of coactivator molecules that amplify the hormone signal and mediate transcriptional initiation. However, AR also undergoes intramolecular interactions that regulate its interactions with coactivators and influence its activity. A large number of naturally occurring mutations of the human AR gene have provided important information about AR molecular structure and intermolecular interactions. AR is also a critical mediator of prostate cancer promotion, conferring growth signals to prostate cancer cells throughout the natural history of the disease. Late-stage prostate cancer, unresponsive to hormonal deprivation, sustains AR signaling through a diverse array of molecular strategies. Variations in the AR gene may also confer genetic predisposition to prostate cancer development and severity. Further understanding of AR action and new strategies to interfere with AR signaling hold promise for improving prostate cancer therapy.