Androgens And The Androgen Receptor

The testis, which produces testosterone, and adrenal glands, which produce androstenedione, dehydroepiandrostene, and dehydroepiandro-stene sulfate, contribute to the bulk of circulating androgens. These are converted in the prostate or peripherally by 5a-reductase to DHT, which is approximately 10 times more active than testosterone.13

Androgens affect both the epithelial and mes-enchymal components of the prostate, regulating growth and differentiation and inhibiting apoptosis. In murine prostates, castration results in glandular atrophy and involution, which is re versed by androgen replacement. The histolog-ical hallmarks of androgen-ablation therapy in the human prostate are atrophy, vacuolation, squamous and transitional cell hyperplasia, and basal cell hyperplasia.14,15 Basal cells are considered to harbor the stem cells of the prostate, not requiring androgens for survival but at the same time able to proliferate and differentiate in response to androgen exposure. In contrast, the terminally differentiated luminal/secretory cells are dependent on androgens for survival and undergo apoptosis when androgens are removed.2,16,17

The AR-signaling cascade is initiated by the binding of androgen (ligand) to the AR.6 The AR is a member of the steroid/nuclear receptor su-perfamily of transcription factors (hereafter designated as NR).18,19 Members of the NR super-family share three major functional domains: a central DNA-binding domain, an NH3 terminal transactivation domain, and a COOH terminal ligand-binding domain.11,20 The DNA-binding domain has two zinc fingers, one to bind DNA and the other to facilitate receptor dimerization as well as binding to coactivators. The NH3 terminal contains one of the two transactivational domains found in the AR, i.e., activator function-1 (AF-1). This region accounts for the greatest diversity that exists between NR members. The AR has polymorphic glutamine and glycine repeats in this region. The COOH ligand-binding domain has a hydrophobic pocket in which the ligand binds. Members of the NR superfamily share a tertiary antiparallel a-helical sandwich with 12 helices, which undergoes conforma-tional changes when the ligand is bound, facilitating coactivator-receptor interactions.21-24 The COOH terminus also has a transcription-activating domain, AF-2, which is active only in the presence of ligand.25 In the inactive state, the COOH terminus of AR is bound to heat shock proteins 70 and 90. Androgen binding leads to dissociation of AR from these heat shock proteins with subsequent phosphoryla-tion, ligand-receptor stabilization, and receptor dimerization. The ligand-receptor complex can then bind to androgen response elements in the promoter regions of target genes. The AR recognizes a consensus glucocorticoid response element (5'-AGAACA-3').26 This activated DNA-bound AR homodimer complex is then able to recruit a plethora of coactivators and corepressors, which interact with the transcriptional machinery, resulting in stimulation or inhibition of target gene transcription. The prototypic androgen-responsive gene in the prostate is PSA.27-30 Other examples of androgen-responsive genes include kallikriens, prostatic acid phosphatase (PSAP), and p21.31,32 Until recently, model systems to study the transition from AD to AI that closely recapitulate the human disease have been lacking. We utilized two human prostate xenografts created in our laboratory, LAPC-4 and LAPC-9, both of which grow and passage successfully in severe combined immunodeficiency disease mice as well as continuously passaged cell lines.33 Both xenografts require androgen for growth, possess a nonmutant AR, synthesize PSA, and progress from AD to AI in response to castration. We demonstrated that a small fraction of cells in these xenografts die by apoptosis in response to castration, whereas the majority withdraw from the cell cycle. These cells remain in a dormant yet viable state and respond rapidly when re-exposed to androgen by re-entering the cell cycle and resuming tumor growth, even 6 months after androgen deprivation. After longer intervals, some LAPC-9 tumors resume growth as AI cancers. Our results suggest that AI progression occurs in two distinct stages.34 At the time of initial diagnosis, a fraction of the cells in a prostate cancer tumor are dependent on androgen for survival and undergo apoptosis in response to androgen-ablation therapy. Clinical evidence for this conclusion has been well documented in studies of prostate cancer patients who receive neoadjuvant hormone-ablation therapy prior to radical prostatectomy. The first step in AI progression is a transition stage in which tumor cells remain androgen-responsive yet no longer require androgen for survival. The second stage involves the outgrowth of a tumor that is independent of androgen for both growth and survival, as observed clinically with hormone-refractory cancers that progress despite androgen blockade. Through serial dilutions and fluctuation analysis of the LAPC-4 and LAPC-9 cell lines, we showed that this second stage results from clonal expansion of a small number of AI cells present in the AD xenografts under selective pressure of androgen ablative therapy (see Color Figure 18.2 in separate color section). Our findings are thus consistent with the hypothesis that hormone-refractory cancer evolves through clonal outgrowth of a small number of AI cells that are preexisting or develop at a low frequency due to secondary genetic mutations. A critical next step is to identify the molecular basis for AI survival as opposed to AD growth.

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