George V Thomas Charles L Sawyers

Androgen-independent prostate cancer is incurable and is responsible for the majority of cancer-related deaths. The intriguing question is how a cancer that is initially exquisitely sensitive to an-drogen-ablation therapy becomes universally refractory to all available forms of such therapy.

Both normal and cancerous prostate cells are dependent on androgens, mainly in the form of testosterone and dihydrotestosterone (DHT), to promote proliferation and inhibit apoptosis.1-3 Androgen mediates its biological actions through the androgen receptor (AR), a ligand-activated transcription factor of the steroid/nuclear receptor superfamily (see Color Fig. 18.1 in separate color insert).4-6 Androgen-ablative treatment modalities rely on either surgical or medical castration, the latter usually administered via luteinizing hormone-releasing hormone (LHRH) analogs (termed monotherapy when used singly) and AR antagonists (termed total androgen-ablative therapy when used in combination).7,8 Counter intuitively, AR continues to be expressed even as the cancer progresses from the androgen-dependent (AD) to an androgen-independent (AI) stage. Immuno-histochemical studies have shown the presence of AR in both AD and AI tumors.9,10 A rise in serum prostatic-specific antigen (PSA), an androgen-regulated gene, is usually the first marker of relapse/development of AI cancer. This suggests that AI prostate cancers rely on expression of AR-dependent genes.11,12

In this chapter, we critically discuss the current mechanistic concepts involved in the development of AI prostate cancer. These mechanisms can be broadly categorized as those known to signal through the AR and those whose mechanism for promoting AI growth remains unclear.

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