Androgen Receptor Coregulators in Prostate Cancer

The transcriptional activity of androgen receptor (AR) is modulated by coregulators that have a significant influence on a number of functional properties of AR, including the ligand specificity as well as the DNA binding capacity. Because androgens and AR have pivotal roles in the development and growth of normal prostate as well as prostate cancer progression, these coregulators may significantly modulate the events of cancer development and progression. An aberrant regulation or expression of AR coregulators may contribute to androgen and AR-related diseases including prostate cancer. A precise understanding of the roles and mechanisms of individual coregulators may provide valuable information in designing rational therapy against prostate cancer. In this review, we analyzed the up-dated information regarding AR coregulators and their potential roles in prostate cancer progression.Androgens play essential roles in male sexual differentiation, sexual maturation, and the maintenance of spermatogenesis (1, 2). In addition to such vital roles in reproductive organ development, androgens also mediate physiological responses in a wide range of other tissues and organs including the skin, skeletal muscle, cardiac muscle, liver, kidney, central nervous system, and the hematopoietic system (3).The prostate gland is one of the main target organs for androgens, which mediate their biological responses through the AR, a Mr 110,000 ligand-inducible transcription factor that regulates tissue-specific expression of target genes. The AR belongs to the nuclear receptor (NR) superfamily, which also includes estrogen receptor, glucocorticoid receptor, progesterone receptor, vitamin D receptor, thyroid receptor, and retinoic acid receptor (4). It is ubiquitously expressed in human organs with the exception of the spleen and bone marrow, which show complete absence of AR expression. The AR gene is composed of eight exons encoding four functional domains similar to other members of the NR superfamily: a conserved DNA-binding domain, a hinge region, a COOH-terminal ligand-binding domain (LBD), and the less conserved NH2-terminal domain [A/B domain (5)]. Mutational and deletion analyses revealed two transcriptional activation functions including an NH2-terminal activation function (AF-1) involved in ligand-independent activation of AR and a ligand-dependent AF-2 function in the LBD. The AF-2 seems to be involved in more general transcriptional activity because mutation or deletion of the AF-2 domain dramatically reduces the transcriptional activation of AR (6, 7).Since cloning of its cDNA structure in 1988 (8), the AR has been extensively studied to elucidate its biological role in the development and progression of prostate cancer. The growth, differentiation, and maintenance of prostate tissue are dependent on AR and androgens, particularly testosterone and dihydrotestosterone (DHT). Overactivation of the AR signaling pathway may link to the progression of prostate cancer, which remains the most frequently diagnosed malignancy in aging men. Androgens and the AR play key roles in this malignancy, and each year about 30,000 men lose their lives to this malignancy in the United States (9). In 1941, Huggins and Hodges (10) first reported that the normal prostate and early stages of prostate cancer were highly dependent on androgens. Since then, androgen ablation, either by surgical castration or by pharmaco-logical/chemical castration, such as treatment with luteinizing hormone-releasing hormone analogs, has been the cornerstone of treatment in patients with locally advanced or metastatic prostate cancer. Androgen deprivation or the blockade of androgens at the level of the AR usually results in a favorable clinical response and a dramatic tumor regression (11, 12). Although complete disappearance of symptoms is achieved initially, in most cases the response does not imply cure. Upon continued treatment, the therapy fails, and most of the patients develop androgen-independent spread of the disease despite androgen ablation. At present there is no effective therapy for such an androgen-independent prostate cancer. One reason for failure of this androgen ablation therapy may be because of the presence of residual adrenal androgens in the circulation. Castration only abolishes testicular androgens, but the circulating adrenal androgens are readily available and can be converted to testosterone or DHT, the more active form of testosterone, in the prostate. To overcome this effect, antiandrogens are given in combination with castration (the so-called maximal androgen blockade therapy) to block the effects of androgens derived from the adrenals. However, support for additional benefit from this combined therapy is controversial, and a recent 5-year survival study failed to offer much hope for prostate cancer patients (13). Even after complete blockade of androgen action, the response to therapy is lost, tumors continue to grow, and the disease progresses into an androgen-independent state (14, 15, 16). The exact mechanisms of such resistance against ablation therapy remain largely unknown.One of the hallmarks of androgen-independent prostate cancer is that tumor growth may still depend mostly on a functional AR signaling pathway. Prostate cancers, even when becoming androgen-independent, may still contain many AR-positive cells. Fig. 1 depicts some of the possible mechanisms as to how AR signaling can operate in both androgen-dependent and androgen-independent prostate cancers. One possible mechanism through which prostate cancer cells circumvent ablation therapy is by hypersensitive AR signaling during androgen ablation therapy, part of which can be due to overexpression of 5α-reductase and AR coactivators in prostate tissues. The 5α-reductase may help tumor cells rapidly convert available testicular androgens into more active DHT, and the coactivators may render AR more sensitive to usually weak adrenal androgens. Prostate cancer cells are then able to survive and grow at very low levels of androgens. The AR-mediated growth despite low androgen levels could also be achieved via an increased expression of AR itself, mostly by AR gene amplification, leading to an enhanced ligand occupied AR. Support for this hypothesis comes from the observation that about a third of tumors that become hormone refractory after ablation therapy have an amplified AR gene, compared with none in the primary tumors from the same patients (17, 18, 19, 20, 21).Another possible mechanism by which prostate cancer cells circumvent the androgen requirement is through the development of mutations in the AR gene. The AR LBD, which is responsible for androgen binding and dimerization, may undergo somatic mutations during prostate cancer progression into the hormone-refractory state (14, 15). Mutations of AR allow the cells to circumvent the normal growth regulation by androgens. The AR ligand specificity becomes modulated and broadened so that the receptor now can be activated by nonandrogenic molecules including androgen antagonists, corticosteroids, and 17β-estradiol (E2). For example, the AR mutant T877A, isolated from patients with advanced-stage prostate cancer, is activated not only by androgens, the normal ligands, but also by antiandrogens, such as hydroxyflutamide [HF (22, 23)]. Another AR mutant, L701H, has been reported to significantly decrease androgen response but significantly potentiate the responses by glucocorticoids (24). The broadening of AR specificity thus seems to offer prostate cancer cells a selective growth advantage to evade androgen ablation therapy.Other growth signaling pathways may cross-talk with the AR signaling pathway and activate AR-mediated growth of prostate cancer cells, bypassing the requirement for androgens. For example, a number of growth factors, including insulin-like growth factor-I, keratinocyte growth factor, epidermal growth factor, and so forth, have been reported to activate AR, inducing AR target genes in the absence of androgens (25). A recent report indicated that interleukin 6 could induce activation of AR via signal transducers and activators of transcription-3. Signal transducers and activators of transcription-3 can physically interact with AR and its transcriptional a signal transducers and activators of transcription-3 mutant interleukin AR a that belongs to the epidermal growth factor receptor of is to be in androgen-independent cells isolated from in have that can modulate the AR response in the absence of androgens or in the presence of low levels of androgens. by the that can activate AR signaling through the pathway revealed that the AR gene binding for and a of AR regulation by these have been by the that A and can activate AR signaling in the absence of androgens of signaling to be with prostate cancer progression the pathway cells to levels of androgens a role of pathway in the of hormone-refractory growth of cancer cells. these that aberrant regulation of AR signaling pathways play a role in progression of prostate cancer. 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