(i) Amplification. Prostate cancer cells develop the ability to utilize low levels of androgen for survival by increased sensitivity of the AR to testosterone (T), by increased local conversion of testosterone to DHT by 5α-reductase, and by increased numbers of ARs. Once DHT binds to AR, the receptor dimerizes and phosphorylates and is transported to the nucleus, where it binds to androgen-responsive elements of genes. This process is modulated by cofactors that act as coactivators and corepressors and results in increased cell proliferation and survival. (ii) Promiscuous pathway. Nonandrogenic steroid molecules normally present in the circulation, as well as antiandrogens, bind and activate the AR. (iii) Outlaw pathway. AR is activated by phosphorylation by nonhormone growth factors through their tyrosine kinase receptors. (iv) Bypass pathway. Prostate cancer cells develop the ability to survive independent of AR. The best-known bypass pathway occurs through upregulation of the molecule Bcl-2 by androgen-independent prostate cancer cells, which protects them from apoptosis. (v) Stem cell regeneration. Prostate cancer stem cells, which are not dependent on the AR for survival, continually resupply the tumor cell population. SHBG, sex hormone–binding globulin; HSP, heat shock protein; GFR, growth factor receptor; P, phosphate group; PTEN, phosphatase and tensin homolog; Grb2, growth factor receptor–bound protein–2; SOS, son of sevenless. Figure modified from Clinical Cancer Research (28).