Androgen receptor signaling in prostate cancer: Genetic and molecular aspects

Abstract

The prostate is an accessory sex gland of the male reproductive system, which produces alkaline prostatic fluid, capable of ensuring the spermatic viability to fertilize eggs within the female reproductive system. Functionally, the prostate is under the control of androgens, such as testosterone and dihydrotestosterone (DHT), and these hormones play a key role in the maintenance of sexual behavior and male reproduction. In prostatic microenvironment, the androgens may directly orchestrate its secretory activity and coordinate events that maintain its morphological integrity. It is noteworthy a dual role of androgens regulating both proliferation and apoptosis of the epithelial cell, suggesting the androgens as having a protective action against pathologic prostate growth. The effects of androgens on prostate are mediated by its androgen receptors (AR), which are expressed by epithelial cells, smooth muscle, and stromal cells. Generally, androgens bind to AR forming the androgen-AR complex that is translocated to the nucleus and regulates gene transcription. Additionally, it has been documented that androgens are able to cause an elevation in both level and half-life of AR. The binding of androgen to AR is an important canonical pathway for regulating the prostatic epithelial differentiation; however, molecular and genetic processes leading to aberrant control of AR pathways are considered a key mechanism for the development of prostate cancer. Androgen deprivation is therefore one of the most common and effective therapies for metastatic prostate cancer, known as androgen deprivation therapy (ADT). It causes regression of androgen-dependent tumors, as documented by Huggins and Hodges, in the 1940s. Nevertheless, in many men, the androgenic ablation therapy can fail and the tumor starts to grow more aggressively, in a stage traditionally called of castration-resistant prostate cancer (CRPC) or as currently referred, hormone refractory or androgen-independent prostate cancer (AIPC). Several cancers that exhibit resistance to ADT have presented defect in AR signaling pathway, which is implicated in hormone-resistant prostate cancer. In this chapter, we will address the molecular and genetic defects involving the AR with focus on the androgen-independent prostate cancer.