Key words: aromatase - CYP19 – tumor promoter - 5-alpha-reductase – cytokines – testosterone – trinucleotide repeat – progression - hormones

Abstract

Prostate Cancer (PCa) is the leading diagnosed malignancy in men in western countries. The relationship between androgens and the androgen receptor (AR) has been studied extensively in PCa. Plasma levels of androgens show variations between different populations, and in many cases this correlates with PCa susceptibility. Indeed, exposure of the fetus to higher androgen concentrations appears to be a risk factor for PCa. The AR is present in the majority of PCa, and its activation by androgens leads to different proliferative, apoptotic and angiogenic events. These events are in turn mediated by dysregulation of cyclin-dependent kinases, apoptotic factors and even mutations in the AR. Although androgen ablation has been the mainstay non-surgical treatment for this disease, most tumors will eventually become refractory to treatment. Different cellular mechanisms appear to be involved in the androgen-independent progression of PCa, including cytokine and growth factor-mediated activation of the AR as well as neuroendocrine differentiation. Thus, an understanding of the cellular mechanisms involved in androgen action may lead to better therapeutic targets for prostate cancer.

INTRODUCTION

Prostate cancer (PCa) is the most frequently diagnosed malignancy and the second leading cause of death as a result of cancer in men in the United States and many other western countries. In the year 2000 there were approximately 190,000 cases diagnosed and 32,000 deaths due to PCa [1]. Steroid hormones, particularly androgens, appear to play a major role in prostate carcinogenesis, but their precise role is not clear. The majority of PCa responds to androgen ablation therapy by temporary remission. However, most tumors will eventually relapse in an androgen-refractory state. This review will address the role of androgens and other factors in the development and progression of PCa.

Metabolism of Androgens

Androgens are required for normal growth and functional activities of the human prostate. Androgen production is regulated by the hypothalamic-pituitary-gonadal axis. Gonadotropin-Releasing Hormone (GnRH) is secreted by the hypothalamus in pulses, thus stimulating Luteinizing Hormone (LH) secretion from the pituitary gland. LH acts on Leydig cells in the testis to induce androgen production.

In men the primary circulating androgen is testosterone. The major portion (95%) is produced by the testis (Leydig cells) and a small amount (5%) is produced by the adrenal gland. The predominant pathway for androgen production in both tissues is the gamma-5 metabolic pathway [2, 5]. Testosterone in circulation is bound primarily by Sex Hormone-Binding Globulin (SHBG) and to a lesser extent by albumin and Corticosteroid-Binding Globulin. Less than 3% of testosterone exists in an unbound bioavailable form. SHBG has the highest affinity for testosterone and therefore plays an important role in regulating the amount of free testosterone available to target tissues [3]. In the prostate, testosterone is converted to the more potent androgen, 5-alpha-dihydrotestosterone (DHT), by the enzyme 5-alpha-reductase. There are two types of 5-alpha-reductase enzymes, type I is present in most tissues of the body, while type II has been reported to be more specific for prostatic epithelial cells [4]. Intracellular DHT is metabolized rapidly to 3-alpha-17B-androstenediol, which can be reversibly converted to DHT or irreversibly converted to inactive triol steroids. It has been suggested that 5-alpha-reductase plays a role in PCa progression [27]. Type II inhibitors are being studied for their therapeutic potential. In this regard, some studies show promising results [6], but other studies show no relation between 5-alpha-reductase inhibitors and PCa [7].

Circulating androgens may be converted to estrogens primarily in fat tissues (80%) by an aromatase enzyme coded for by the CYP19 gene [8]. This gene is expressed in the human prostate, suggesting a local source of estrogen for the prostate. Intraprostatic production of estrogens has been related to benign prostate hyperplasia (BPH) [9]. However, a role of estrogens in prostate carcinogenesis is still uncertain.

Androgens-androgen receptor interaction in normal prostate

Free testosterone enters the prostate cell, where it is converted to DHT by 5-alpha-reductase. Both testosterone and DHT can bind to the androgen receptor (AR) in the nucleus. However DHT forms a more stable receptor-ligand complex and is 3 to 10 times more potent [2]. Once the AR binds to androgen it enters an active state and undergoes transactivation. The major function of the AR is to induce growth of the male urogenital structures.

The AR, which is a member of the steroid receptor superfamily [10], is composed of three domains: 1) the transcriptional activation domain, 2) the DNA-binding domain, and the androgen-binding domain in the C-terminal end [2]. Reversible phosphorylation appears to play a role in both ligand-dependent and ligand-independet activation of the AR [4, 11]. Twenty one potential phosphorilation sites have been identified in the AR [12]. The AR directs the assembly and stabilization of the basal transcription apparatus and androgen-dependent co-factors like ARA70, ARA54, ARA55, and CREB binding protein (CBP) [13] at target gene promoters, thus enhancing transcription [10].

Androgen receptors can form either homodimers or heterodimers with other proteins that regulate their biologic properties [2]. The zinc finger region mantains a conformational structure of the AR that is necessary for binding to specific DNA regions, termed androgen-responsive elements (ARE). This interaction allows activation of androgen-responsive genes.

Epidemiology of androgens and prostate cancer
The relationship between levels of steroids and risk of prostate cancer in different populations has been studied extensively. A comparative study between African-American men and African men found that levels of testosterone were significantly increased in the African-American group, though the levels of DHT and estradiol were similar [14]. A study of androgen levels in three different groups: African-American, European-American, and Black South-African men found that levels of dehydroepiandrosterone (DHEA) were lower in black men than in white men, whereas estrone levels were higher. Plasma levels of androstenedione (a testosterone processor) were higher in African men than in European-American and African-American men, whereas no difference was found in testosterone levels. Although the findings from this study were partially contradictory with other studies, there were differences in the ages of the populations studied [15, 16].

Approximately 15% higher levels of total and free testosterone were found in African-Americans compared to European-Americans in the U.S. This difference may explain the two-fold difference in prostate cancer risk between these populations [17]. Circulating levels of testosterone in African-American and European-American pregnant women during the first trimester of pregnancy have been compared. African-American women had 47% higher levels of testosterone, suggesting that in this population the fetus is exposed to higher concentrations of androgens before birth [18].

Hormone levels of American men and European men (both at high risk for PCa) were compared to Japanese and Chinese men (low risk for PCa). Even though European men showed a difference in testosterone levels when compared to Asiatic men, no clear differences were observed between American men and Asiatic men. Lower 5-alpha-reductase metabolized androgens and SHBG in the Asiatic population were observed in all of these studies [19, 20, 21, 22]. Androgens appear to play a major role in the carcinogenesis of prostate cancer. Most attention has been focused on DHT. Some findings suggest that 5-alpha-reductase activity is reduced in the Asian population consequently reducing DHT and androgen-mediated stimulation of the prostate. Also, there is a polymorphism in the 5-alpha-reductase gene present in Asians that could be associated with less 5-alpha-reductase activity [21, 23]. However, no difference was found in a study where overall conversion of testosterone to DHT was measured with intravenous isotope dilution [24]. Thus, studies of ethnical/racial groups provide evidence that levels of androgens play a role in the incidence of PCa. However, no substantive evidence supports the hypothesis that elevated 5-alpha-reductase levels increase the risk of PCa

The AR and its role in prostate cancer
Sixty years ago Huggins et al reported that castration significantly reduces levels of acid phosphatase (a prostate disease marker) in patients with prostate cancer, indicating the androgenic dependence of these tumors [46]. Since then, androgen ablation therapy has been the primary treatment for metastatic PCa. Different therapies include orchiectomy or LHRH analogues (both with the purpose of reducing testosterone levels), antiandrogen treatment with flutamide or bicalutamide (which interfere with androgen binding to the AR), and maximal androgen blockade (MAB) that combines androgen ablation with antiandrogen treatment [25, 26].

Several advances have been made recently to elucidate the mechanism by which androgens regulate PCa through the AR. The AR is present in the majority of PCa both at the primary and metastatic sites regardless of stage and grade, as well as in hormone refractory cancers [27, 28]. Although there appears to be no correlation between AR immuno-reactivity and disease prognosis, some studies have suggested that an increase in heterogeneity of AR expression may be associated with higher grade or poorer prognosis [29, 30, 31]. A recent study from our laboratory suggests that AR function may play a major role in the proliferation of androgen-refractory PCa cells [32].

Activation of the AR in both normal prostate and PCa leads to complex proliferative, apoptotic and angiogenic events. Androgens enhance expression of cyclin-dependent kinases 2 and 4, as well as induce down regulation of the cell cycle inhibitor p16 in cells expressing AR, whereas in androgen-independent cells there is no difference in expression of these proteins upon androgen stimulation [33]. The overall effect of androgens in cells expressing AR is an increase of cyclin-dependent kinase activity and stimulation of cells to enter S phase of the cell cycle, thereby enhancing cell proliferation. Androgens up-regulate p21, an anti-apoptotic factor, suggesting that androgens may be inducing anti-apoptotic activity [34]. In this regard, p21 is increased significantly in advanced, high Gleason score PCa [35]. Androgens may block apoptosis by inhibiting caspase activation in both extrinsic and intrinsic cell death pathways, thus promoting the growth of PCa [36].

More than 300 mutations of the AR have been described. Most of these mutations occur in the ligand-binding domain. Although the majority of these mutations are described in patients with androgen insensitivity syndrome (AIS), at least 60 mutations have been described in PCa. Mutated ARs may have altered binding for testosterone and DHT and may even be able to stimulate growth after testicular androgen ablation, since they can bind to adrenal androgens, DHT metabolites, etc. However, several studies show low frequency of AR mutations in prostate cancer [37, 38]. Thus, the frequency of mutation appears to increase with the stage of PCa, being low in organ-confined disease and higher in metastatic disease [39].

Within the amino-terminal transactivation domain of the AR there are three trinucleotide repeats. Two of them, CAG and GGN show a polymorphism that has been studied widely. Because the majority of PCas are AR positive, polymorphic differences may affect cancer risk and clinical progression. Shorter polyglutamine CAG repeat length polymorphisms are associated with increased PCa risk [4]. These alleles are found most commonly in African-American males and less frequently in European-American males [40]. Alterations in the number of CAG repeats have been found to correlate with altered AR transcriptional activity. Either shortening or elimination of the tract results in elevated AR activity suggesting that the expansion of CAG-repeats decreases AR transcriptional activity [41]. Since AR with shorter CAG repeat length are more prevalent in racial groups with higher PCa risk, it may be hypothesized that racial differences in PCa is the result of variability in the CAG repeat of the AR [42]. Also, the association of short CAG trinucleotide repeats and increased AR transcription, suggests that early tumorigenesis is dependent on a more active AR. Although the GGN polymorphism has been associated with PCa, the studies are conflicting and variable [40, 43].

The 5alpha-reductase type II enzyme is produced from the SRD5A2 gene [44]. Population-based screening assays have shown that the presence of mutations in this gene correlates with PCa risk in different ethnic groups [27]. At least two mutations (V89L and A49T) in this gene have been identified [42, 45]. It has been suggested that polymorphisms in the SRD5A2 gene can affect the intra-prostatic levels of DHT and risk of developing PCa [42]. In summary, the genesis and progression of PCa likely requires a functional AR. Thus an AR with a higher trans-activating potential may be a promoter of these events. Polymorphic differences and mutations that results in hypersensitivity or gain in function of the receptor, provide a plausable mechanism of cancer progression.

Androgen-refactory prostate cancer
Although PCa responds initially to androgen ablation therapy, most tumors eventually recur in an androgen refractory manner [64]. In this regard, the AR is expressed in nearly all cancers of the prostate, both before and after androgen ablation therapy [47, 48, 49]. Several mechanisms that may contribute to the progression of PCa to an androgen refractory state have been described [13]. Mutations in the AR may allow it to respond to different steroids as well as antiandrogens [50, 51, 52]. Also, AR signaling can be enhanced by peptide growth factors and cytokines in a ligand-independent manner. For example, insulin growth factor 1 (IGF-1) and keratinocyte growth factor (KGF) are able to promote AR transcriptional activity in vitro in the absence of androgens [53]. Also, IGF-1 is associated with increased PCa risk [54, 55]. Other cytokines and activating factors like interleukin-6 (IL-6), forskolin, cyclin E, and butyrate can activate the AR pathway in the absence of androgens [56, 57, 58, 59]. IL-6 is of particular interest since the plasma levels of this cytokine are increased in patients with androgen refractory PCa [60, 61]. IL-6 has been shown to activate the AR in the absence of androgens through the MAPK pathway [62]. Data from our own laboratory suggests that the co-activator p300 is essential for this interaction (Debes et al, Proceedings AACR, Vol 43, March 2002).

Even though the AR may play a role in the progression to androgen refractory PCa [32, 63], there might be different pathways that bypass the AR. This could be the case in neuroendocrine differentiation of PCa. Several studies suggest that NE cells may contribute to the progression to androgen refractoriness through the production of neurosecretory products, like serotonin, bombesin, chromogranin A, neurotensin and parathyroid hormone-related peptide [65, 66, 67, 68]. Thus, cytokines are likely to provide the cells with growth stimulatory signals and may contribute to PCa progression.

Conclusions
Androgens acting through the androgen receptor play important roles in prostate cancer. Evidence suggests that increased transactivation activity of the AR may be associated with increased risk of prostate cancer. It is known that African-American men have a two-fold higher risk of developing prostate cancer than European-American men. Important factors may include modifications in their hormonal status, which may act as early as the in utero stage.

Thus, it may be hypothesized that androgens act as tumor promoters via androgen receptor-mediated mechanisms, which leads to enhanced cell proliferation and decreased apoptosis. All of these processes are modulated by a variety of factors and genetic determinants that encode enzymes and receptors involved in the metabolism and action of steroid hormones. Although androgens are strongly implicated in prostate carcinogenesis, considerable research is needed to further understand this relationship. Additional work is needed to clarify the biologic mechanisms underlying the increased risk associated with elevated circulating androgen levels and androgen receptor sensitivity as well as the roles that androgens are playing in the progression of PCa.

Acknowledgements
Supported in art by grants from the NIH (CA91956, DK60920), the T.J. Martell Foundation, and the Yamanouchi Foundation.

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