Figure 1. The road to (androgen) independence.

AR-negative prostate adult stem cells generate AR-negative transit amplifying cells, AR-negative intermediate cells and AR-positive luminal secretory cells. Once therapeutic circulating androgen blockade ensues, AR-positive luminal cells die, giving origin to the adaptive (selected AR-positive luminal cells will continue to thrive despite lack of androgen exposure) and clonal theory of resistance (pre-existent AR-negative cells develop into a malignant clone). Castration-resistant prostate cancer might develop via ligand-dependent (tissue steroidogenesis, AR mutations, AR amplification) and ligand-independent pathways (heightened AR nuclear translocation, AR cross-talk with additional pathways, disturbing the balance between co-activators and co-repressors).