Multiple genetic changes are required to produce prostatic cancer cells that can metastasize and kill the patient (1, 2). The most fundamental consequence of these molecular abnormalities is that the rate of malignant prostate cell proliferation exceeds its rate of cell death (3). It is this disruption of cellular homeostasis that results in the continuous net growth producing the lethality of this devastating disease. Successful therapy for the 30,000 US males dying of prostate cancer annually will require approaches that shift the cell kinetic balance such that the rate of prostatic cancer cell death exceeds cell proliferation without producing unacceptable host toxicity. To have a realistic chance of developing such successful therapy, identification of the molecular changes driving the imbalance in proliferation vs. death of malignant prostate cells is critical.

Androgens are the major growth factors for the normal prostate, and its cognate receptor is fundamental for androgen signaling within the gland (4). Prostate cancers retain androgen receptor (AR) signaling pathways and thus are nearly universally responsive initially to androgen ablation therapy. Unfortunately, however, essentially all ablated patients eventually relapse. Because of this relapse, androgen ablation therapy is not curative, no matter how complete the ablation (5). A growing body of data has documented that this is due to the accumulation of molecular changes inducing gain of function in the AR signaling pathways during the progression of prostatic cancer. These gain of function changes result in prostate cancer cells that are resistant to androgen ablation because of their acquired ability to activate novel AR signaling pathways for their proliferation and survival without requiring physiological androgen ligand binding. These changes produce malignancy unique signaling pathways that, while androgen ligand-independent, are