Androgen Transactivation Pathways

Beta Switch Program

The Beta Switch Program by Sue Heintze

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Androgens play a critical role in normal and abnormal prostate development. Studies of androgens and prostate cancer go back nearly 60 years. The pioneering work of Huggins in this area was rewarded with a Nobel prize. Substantial epi-demiological data support a critical role for an-drogens in prostate cancer etiology.2,3 Prostate cancer development is absent in men with marked androgen deficiency, such as eunuchs, or men with markedly reduced androgenization of the prostate, such as those with constitutional absence of 5a-reductase enzyme activity in whom the prostate remains a vestigial organ. Normal prostate development is induced by de-

hydrotestosterone (DHT), which is formed from testosterone (T) by the enzyme steroid 5a-re-ductase.41 In men, T is produced in large amounts primarily by the testes. It is then irreversibly metabolized intracellulary to DHT. The DHT (or, much less efficiently, T) is bound by an intracellular cytosolic receptor, the androgen receptor (AR). This complex is then translocated to the cell nucleus, where it activates transcription of genes with androgen-responsive elements (AREs) in their promoter regions.

Ross and colleagues3 introduced the concept of a polygenic etiology of prostate cancer related to multiple functional polymorphic variants in genes involved in androgen biosynthesis, transport, activation, and metabolism. They proposed that each such variant might have only a minor impact on androgen transactivation and, therefore, on prostate cancer risk but that multiple such variants in combination might have a more substantial impact. This group also introduced the notion that there might exist multiple polymorphic variants in the same gene, which might either act jointly in their impact on androgen transactivation activity or even "cancel" each other out.

To date, only a few genes in this pathway have been studied in relationship to prostate cancer risk (Table 15.2). Two of these have been particularly well studied, the 5a-reductase type II (SRD5A2) gene, which encodes the enzyme that

Table 15.2. Characteristics of Selected Androgen-Metabolic Genes

Gene Symbol Gene Product Chromosomal Location Gene Size (kb)

AR Androgen receptor Xq11-12 >54

CYP17 Cytochrome P-450c17 10q24.3 8.7

HSD3B2 3J8-Hydroxysteroid dehydrogenase 1p13 7.8

HSD17B3 17^-Hydroxysteroid dehydrogenase 9q22 >60

SRD5A2 Steroid 5a-reductase 2p23 >40

activates T in the prostate to its reduced and more biologically active form, DHT, and the AR, which binds DHT and then transports the ligand-receptor complex to the nucleus for DNA binding and transactivation of androgen-responsive genes.

The SRD5A2 gene is located on chromosome 2, spanning 40 kb with five exons (Fig. 15.2).42 Steroid 5a-reductase is a membrane-bound enzyme that catalyzes the irreversible conversion of T to DHT with reduced nicotinamide adenine dinucleotide phosphate (NADPH) as a co-factor.41 Two isozymes exist: the type I enzyme with an alkaline pH optimum, encoded by the SRD5A1 gene, and the type II isozyme with an acidic pH optimum, encoded by the SRD5A2 gene.43 Thigpen et al.43 reported immunological studies showing that the type I enzyme is expressed primarily in newborn scalp and in skin and liver. The type II isozyme protein is expressed primarily in genital skin, liver, and prostate. Molecular genetic studies have shown that a rare disorder of male sexual differentiation, male pseudohermaphroditism, is due to 5a-reductase deficiency and inactivating germline mutations in the SRD5A2 gene.42 Affected males exhibit genital ambiguity and external fe male phenotype until puberty, at which point there is some development of secondary sex characteristics but the prostate remains highly underdeveloped.44 Thus, normal prostate development requires normal function of the SRD5A2 gene.

Reichardt and colleagues45 initially screened the gene for polymorphic variants among a population with either high or low circulatory levels of androstanediol glucuronide, a DHT metabolite and a circulating correlate of 5a-reductase activity in the prostate. This process initially yielded eight single-nucleotide substitution polymorphisms, i.e., variants resulting in an amino acid change in the protein product, as well as several silent polymorphisms, i.e., single-nucleotide variants resulting in no amino acid change.45 This group also described a series of previously unknown variants of a dinucleotide (TA) repeat sequence in the 3'-untranslated region (UTR) of the gene.46 Reichardt's group proceeded to characterize the eight substitution polymorphisms in vitro using transfection assays to assess enzyme activity versus wild-type.47 Although a few of these were true polymorphisms, resulting in no detectable change in enzyme activity despite the amino acid change in the pro

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