Abstract

An American man is diagnosed with prostate cancer (PC) every 3 min and dies from the disease every 17 min. Although androgen receptor (AR) expression is diminished following androgen deprivation therapy (ADT) that induces clinical remission in most patients, castration-recurrent PC expresses levels of AR protein similar to those found in androgen-stimulated PC and benign prostate. This observation suggests that the AR may be as important for growth regulation in castration-recurrent PC, as it is in androgen-stimulated PC and benign hyperplasia. Neither ligand-independence, point mutations, glutamine and/or glycine repeat expansion nor amplification have explained AR activation in most cases of castration-recurrent PC. Castration-recurrent PC tissue has levels of testosterone (T) similar to androgen-stimulated benign prostate and levels of dihydrotestosterone (DHT), the most active androgen for AR activation that are approximately 10% of androgen-stimulated benign prostate. These levels of tissue androgens appear capable of activating the AR since prostate-specific antigen (PSA), the classic androgen-regulated gene, is expressed at similar tissue levels in castration-recurrent and androgen-stimulated PC. These startling findings suggest a paradigm shift; PC that recurs during ADT is not androgen-independent.