© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 22, 1687-1697,
November 21, 2001
© 2001 Oxford University Press
REVIEW |
Androgen Receptor Signaling in Androgen-Refractory Prostate Cancer
Affiliations of authors: M. E. Grossmann, H. Huang (Department of Urology), D. J. Tindall (Departments of Urology and Biochemistry/Molecular Biology), Mayo Clinic, Rochester, MN.
Correspondence to: Donald J. Tindall, Ph.D., Departments of Urology and Biochemistry/Molecular Biology, Mayo Clinic, Guggenheim 17, 200 1st St., S.W., Rochester, MN (e-mail: Tindall{at}mayo.edu).
 |
ABSTRACT |
|---|
 Top Abstract IntroductionAndrogens and the Androgen...Prostate Cancer Progression and...Mechanisms for Progression to...ConclusionReferences |
|---|
Prostate cancer is the second most prevalent cancer in males in the United States. Standard therapy relies on removing, or blocking the actions of, androgens. In most cases, this therapy results in a regression of the cancer because the prostate and most primary prostate tumors depend on androgens for growth and the avoidance of apoptosis. However, a portion of the cancers eventually relapse, at which point they are termed "androgen refractory" and can no longer be cured by conventional therapy of any type. The precise molecular events that lead from androgen-sensitive prostate cancer to androgen-refractory prostate cancer are, therefore, of great interest. This review seeks to identify specific molecular events that may be linked directly to the progression to androgen-refractory cancer. Some of the mechanisms appear to involve the androgen receptor (AR) directly and include mutations in, or amplification of, the AR gene in a manner that allows the AR to respond to low doses of androgens, other steroids, or antiandrogens. In a less direct manner, coactivators may increase the sensitivity of the AR to androgens and even other nonandrogenic substances through a number of mechanisms. Additional indirect mechanisms that do not result from mutation of the AR may involve activation of the AR by peptide growth factors or cytokines or may involve bypassing the AR entirely via other cellular pathways. Identification of the role of these mechanisms in the progression to androgen-refractory prostate cancer is critical for developing therapies capable of curing this disease.
|
INTRODUCTION |
|---|
|
TopAbstractIntroductionAndrogens and the Androgen...Prostate Cancer Progression and...Mechanisms for Progression to...ConclusionReferences |
|---|
The second most common cancer diagnosed in U.S. males, after nonmelanoma skin cancer, is prostate cancer. Estimates are that, in 2000, 180 400 cases of prostate cancer were diagnosed in the United States and 31 900 men died of the disease (1–3). Withdrawal of androgens through physical or chemical castration often leads to regression of the disease. This regression is, however, often transient, and there is no known cure for prostate cancer after it has become metastatic and androgen refractory. It is still unclear why many prostate tumors eventually become androgen refractory. This review will describe the molecular mechanisms that may be involved in the progression to androgen-refractory prostate cancer.
|
ANDROGENS AND THE ANDROGEN RECEPTOR IN NORMAL PROSTATE |
|---|
|
TopAbstractIntroductionAndrogens and the Androgen...Prostate Cancer Progression and...Mechanisms for Progression to...ConclusionReferences |
|---|
Androgens are produced primarily in the form of testosterone by Leydig cells in the testes and are generally found circulating throughout the body (4). In addition, adrenal androgens, such as androstenedione, dehydroepiandrosterone (DHEA), and its sulfate, are secreted by the adrenal cortex; although not as potent as testosterone, adrenal androgens do contribute to androgenic effects in the body. Production of androgens in the Leydig cells is regulated through the hypothylamic–pituitary–gonadal axis. The hypothalamus secretes pulses of gonadotropin-releasing hormone (GnRH) every 90–120 minutes. GnRH binds to gonadotropes in the anterior pituitary and stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone. When LH reaches the Leydig cells, it stimulates production of androgens, which, in turn, feed back on the pituitary to inhibit the secretion of GnRH and LH.
The androgen receptor (AR) is a phosphoprotein that mediates the actions of testosterone and dihydrotestosterone (DHT) by acting as a transcription factor (4). The AR is found in many tissues of both sexes but is most abundant in male sex tissues. The best characterized functions of the AR are to promote the growth and differentiation of the male urogenital structures. It is also essential for the initiation and maintenance of spermatogenesis. The AR is a member of the steroid receptor superfamily (5) and is composed of three major domains: an N-terminal transcriptional activation domain, a central DNA-binding domain, and a C-terminal steroid-binding domain. Once testosterone has entered the cell, it is usually converted to DHT by 5
-reductase. The AR is capable of binding to both testosterone and DHT, although DHT has a higher affinity for the AR (approximately twofold to 10-fold) and is consequently the primary androgen bound by the AR. The AR is also capable of being phosphorylated, and reversible phosphorylation appears to play a role in both ligand-dependent and ligand-independent AR activation (4). Before binding its ligand, the AR is thought to be in an inactive state, in which it is bound to at least three heat-shock proteins (hsp90, hsp70, and hsp56) (6). Once the AR has bound DHT, some of these proteins dissociate, and there is a conformational change in the AR. The AR then interacts with coactivators, such as the AR-associated 160-kd protein, ARA70, ARA55, ARA54, and cyclic adenosine monophosphate (cAMP) response element-binding protein-binding protein (CBP). It then binds as a homodimer to a specific DNA site, the androgen response element, in the promoter of androgen-responsive genes, to activate transcription of these genes.
|
PROSTATE CANCER PROGRESSION AND THE AR |
|---|
|
TopAbstractIntroductionAndrogens and the Androgen...Prostate Cancer Progression and...Mechanisms for Progression to...ConclusionReferences |
|---|
More than 99% of prostate cancers develop from glandular epithelial cells in the prostate and are, therefore, described as prostatic adenocarcinomas. A number of molecular events occur in the progression to initial tumor formation in most cancers (7). These events include abnormal methylation, proto-oncogene activation, inactivation of DNA repair mechanisms, inactivation of tumor suppressors, and an increase in the synthesis and activity of growth factors and growth factor receptors (8). These events lead to an infinite growth potential for the tumor cells. It is possible that prostatic intraepithelial neoplasia is an early stage of prostate cancer, although definitive proof of this hypothesis is still lacking. Benign prostatic hyperplasia (BPH), however, is clearly not related to prostate cancer (9). As prostate cancer progresses, it eventually escapes the prostatic sheath and metastasizes to lymph nodes and bone. During the time that the tumor cells are escaping the sheath and metastasizing, they must develop the abilities to evade apoptosis, invade tissues, and produce new blood vessels.
A unique requirement for prostate cancer is the initial reliance on androgens for growth and to avoid apoptosis (10). Because of this requirement, standard therapies block the action of androgens or remove the testicular androgens from the patient (endocrine therapy). These therapies include orchiectomy to physically lower testosterone levels and injections of LH-releasing hormone analogues to pharmacologically lower testosterone levels (androgen ablation); treatment with antiandrogens, such as flutamide or bicalutamide, to block testosterone binding to the AR (antiandrogen therapy); and maximal androgen blockade (MAB), in which antiandrogen treatment and androgen ablation therapy are combined. However, although many tumors initially regress after such therapies, most of the tumors eventually begin to regrow at various rates in an androgen-refractory manner. This change to androgen-refractory growth may be due to an evolution of the cancer, whereby the minority of cells that are androgen refractory before antiandrogen or androgen ablation therapy have a selective advantage relative to the androgen-sensitive cells. Of interest, studies on patient specimens (11–16) show that the AR is expressed in nearly all cancers of the prostate, both before and after androgen ablation therapy. In fact, prostate-specific antigen (PSA), which is encoded by an androgen-responsive gene, has been detected in the majority of hormone-refractory cancers, indicating that the AR-signaling pathway is still functional in these cancers.
To investigate the progression to androgen-refractory prostate cancer, a number of androgren-refractory model systems have been established (17–26) (Table 1
). These cell lines, xenograft models, and transgenic animals are being utilized currently to elucidate the details of the progression to androgen-refractory prostate cancer. There is much that these models can reveal. For instance, a recent complementary DNA microarray analysis of 5184 genes in both hormone-refractory CWR22R xenografts and the hormone-sensitive parental line CWR22 revealed that only 37 genes increased in expression in the xenografts more than twofold (27). Corroboration that the genes are expressed at higher levels in androgen-refractory prostate cancer through further array analysis by use of other androgen-refractory prostate cancer models should provide a clearer picture of the progression to androgen-refractory prostate cancer.
|
|
MECHANISMS FOR PROGRESSION TO ANDROGEN-REFRACTORY PROSTATE CANCER |
|---|
|
TopAbstractIntroductionAndrogens and the Androgen...Prostate Cancer Progression and...Mechanisms for Progression to...ConclusionReferences |
|---|
Prostate tumor cells appear to have several possible mechanisms by which they could become androgen refractory. First, mutations in the AR hormone-binding domain or amplification of the AR gene could increase tumor cell sensitivity to the very low levels of androgens that are produced by the adrenal glands. Second, mutations of the AR could allow it to respond to other steroids or even to antiandrogens. Third, alterations of the interactions between the AR and some of its coactivators could allow unmutated or mutated AR to become activated by adrenal androgens, other steroids, or antiandrogens. Fourth, alterations in the expression or function of genes in regulatory pathways involving peptide growth factors or cytokines could cause inappropriate activation of the AR. Fifth, the AR could be bypassed entirely, possibly as a result of constitutive activation of regulatory molecules downstream of the AR. For example, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) inactivation, p53 mutations, Bcl-2 pathway alterations, neuroendocrine (NE) factors, and alternative growth factor regulation and utilization could all bypass the need for activation of the AR. A careful examination of these five mechanisms reveals that the AR, or at least the AR-signaling pathway, is a critical component of all of them. In addition, these mechanisms to androgen-refractory prostate cancer are not necessarily mutually exclusive; indeed, it is likely that no single mechanism will be utilized in every case of androgen-refractory prostate cancer. Therefore, the remainder of this review will elucidate these mechanisms to androgen-refractory prostate cancer, the possible interactions among these mechanisms, and the potential roles of these mechanisms in the development of androgen-refractory prostate cancer.
Mutation or Amplification of the AR to Increase Its Sensitivity to Androgens
It has been suggested that mutations in the AR may allow it to bind and be activated by ligands that are normally present in the body (e.g., adrenal androgens) but that do not normally cause substantial activation of the AR (28). These gain-of-function mutations would allow the prostatic epithelial cells to grow in an androgen-refractory manner. The gain-of-function mutations found in prostate cancer can be contrasted to the loss-of-function mutations that occur in androgen-insensitivity syndrome and that prevent specific developmental and growth events from occurring. The adrenal androgen DHEA is bound by two AR mutants, T877A and H874Y (29). T877A was initially described in the LNCaP cell line, and H874Y is found in the androgen-refractory prostate cancer xenograft CWR22. Both mutations lead to a transcriptional response to DHEA that is severalfold higher than that of wild-type AR.
A number of mutant ARs that allow cells to respond to adrenal androgens have also been identified directly in tumors of patients who have failed to respond to antiandrogen therapy (30). These mutations appear to occur in only a minority of patients but may account for some cases of androgen-refractory prostate cancer. One such mutation, V715M, results in activation of the AR by the adrenal androgens DHEA and androstenedione (31). Therefore, although the clinical implications of the in vitro data remain undetermined at this time, it is possible that, in a minority of cases, the utilization of adrenal androgens may provide the prostate cancer cells that have these types of mutations with a selective growth advantage during antiandrogen therapy.
Another means by which prostate cancer cells seem to be able to gain a growth advantage that does not involve mutation of the AR gene itself is through amplification of the AR gene. Several studies (32,33) have now used fluorescence in situ hybridization to show that, whereas the AR is rarely amplified in primary prostate cancer, it is amplified in 22%–30% of androgen-refractory prostate cancers. The amplification can take place during treatment with antiandrogens such as bicalutamide (34). In one example, a tumor was found to have an amplified AR after the patient had undergone treatment with the 5-reductase inhibitor finasteride to relieve the problems associated with the enlargement of the prostate that occur with BPH (35). In another study (36), fluorescence in situ hybridization analysis of 371 tumor specimens revealed that the AR was amplified in 22% of metastatic prostate cancers and in 23% of local recurrent androgen-refractory prostate cancers but in fewer than 2% of the primary prostate cancers. Moreover, other genes examined (cyclin-D, ERBB2, N-MYC, and MYC) showed a much lower prevalence of amplification (0%–8%), indicating that the AR amplification is not a generalized occurrence. These data illustrate that, following the progression from an androgen-sensitive to an androgen-refractory state, the percentage of tumors with AR amplified at the genomic level increases.
The biologic role of the amplified AR gene is currently under investigation. Initial evidence indicates that the increased levels of AR DNA are associated with an increase in AR messenger RNA (33). Increased levels of AR protein associated with AR gene amplification have been implicated in the ability of cells to more effectively use the low levels of androgens that are still available during androgen deprivation therapy (37). A surprising finding was that AR amplification is often seen in recurrent tumors of patients who initially respond well to androgen deprivation therapy and in patients whose responses last more than 12 months (33). It was also reported that one patient with AR amplification after tumor recurrence had undergone MAB, which resulted in good initial treatment response that was, however, short-lived. Similar short-term responses after MAB have been documented in 20%–35% of unselected patients who received MAB therapy after failure of castration (38,39). It is possible that these patients had similar AR amplification, although this has not been determined.
It was unexpected that recurrent tumors with AR amplification would follow those primary tumors that had initially responded better to endocrine therapy. One explanation is that the recurrent tumors are dependent on androgens and, therefore, an increase in AR copy number allows them to once again proliferate in response to low levels of androgens. Therefore, if these recurrent cells are still highly hormone dependent, that would explain their response to MAB. The data also suggest that more than one survival mechanism is used by the prostate cancer cells in this setting and, therefore, probably in other settings, since not all patients responded similarly. AR amplification is not seen in all androgen-refractory prostate cancers, but it may play a role in a minority of cases.
While initial studies linked AR amplification alone to androgen-refractory prostate cancer, additional research has shown that AR amplification is also positively associated with immunostaining for mutant p53. One study (40) showed that 75% of androgen-refractory prostate cancers that had p53 mutations also exhibited AR amplification, whereas only 27% of androgen-refractory prostate cancers that had wild-type p53 did so. It is possible that the inactivation of p53 may lead to amplification of the AR through genetic instability. However, an alternative explanation may be that AR amplification leads to mutation and inactivation of p53. Further studies into the basic role of the AR in normal prostate, androgen-sensitive prostate cancer, and androgen-refractory prostate cancer will be necessary to fully elucidate the biologic role of amplified AR in androgen-refractory prostate cancer and the clinical implications. However, it is clear that AR is more highly amplified in androgen-refractory prostate cancer as compared with androgen-sensitive prostate cancer, and it seems likely that this difference, in turn, results in androgen-refractory prostate cancer cells being able to better utilize low levels of androgens.
Mutation of the AR to Permit AR Activation by Other Steroids and Antiandrogens
Mutations in the ligand-binding domain of the AR could not only increase sensitivity to normal ligands, such as adrenal androgens, which are present at low levels, but also may cause the AR to be responsive to other molecules, such as antiandrogens, which are not normal ligands. For example, in the early 1990s, an interesting phenomenon was reported in a few patients who had been undergoing therapy with the antiandrogen flutamide. In those patients, PSA levels declined after treatment was discontinued. Discontinuation of treatment with other antiandrogens, including bicalutamide, chloradinone acetate, megestrol acetate, diethylstilbestrol, and estramustine phosphate, has also been found to lead to PSA declines (41–44). This effect is now defined as endocrine withdrawal syndrome or antiandrogen withdrawal syndrome (41–44). The biologic consequences of the fall in PSA after antiandrogen withdrawal are unknown. However, although PSA levels are generally indicative of tumor burden, it is clear from bone scans that tumor progression can occur, even when PSA levels are declining (45).
Point mutations in the AR may account for the antiandrogen withdrawal syndrome (31,42); some of these mutations are included in a database of AR mutations on the Internet (46). Some mutations in the AR can result in the AR being activatable by both adrenal androgens and by antiandrogens and other steroids. For example, a number of cases of androgen-refractory prostate cancer have been reported to contain a mutation of AR at codon 877 (T877A) (47,48), the same mutation that is found in the human prostate cancer cell line LNCaP (49). This mutant AR not only is activatable by adrenal androgens but also binds the antiandrogen hydroxyflutamide in a manner that leads to fourfold to sevenfold greater agonistic activity than hydroxyflutamide binding to wild-type AR. Of interest, the same mutation can also render cells more responsive to both estradiol and progesterone than cells with wild-type AR. Some patients with this mutation have shown remarkable declines in PSA levels after antiandrogen withdrawal (49). Therefore, these data support the hypothesis that point mutations in the AR, particularly in the hormone-binding domain, may be responsible for some cases of androgen-refractory prostate cancer by allowing the AR to continue to be activated by antiandrogens.
Coactivators and Androgen-Refractory Prostate Cancer
A number of coactivators interact directly with the AR and enhance AR-dependent gene transcription. A comprehensive list of proteins that interact with the AR is available on the Internet (46). Some of the better characterized coactivator proteins are members of the 160-kd nuclear receptor coactivator (p160) family, including glucocorticoid receptor-interacting protein 1, the steroid receptor coactivator-1, and the receptor-associated coactivator-3 (50). These coactivators interact with the N-terminal activation domain of the AR (51). The p160 coactivators can also bind to the ligand-binding domain of the AR, thereby enhancing ligand-dependent, AR-mediated transcription of target genes (52). It has recently been shown that the BRCA1 protein can interact physically with the p160 coactivators and the AR, although whether these interactions occur simultaneously is not known (53). In addition, BRCA1 can enhance AR-dependent transactivation of an AR-responsive promoter by an unknown mechanism (53). The possible roles of the p160 coactivators and BRCA1 in androgen-refractory prostate cancer have yet to be determined, but one possibility is that an increase in the protein levels of the p160 coactivators or BRCA1 may allow adrenal androgens to function more efficiently as AR ligands.
Members of a second group of coactivators alter the ligand specificity of AR activation. These coactivators include the AR-associated proteins ARA54, ARA55, and ARA70 (also known as RFG and ELE1) (54–56). ARA55 and ARA70 both allow activation of the AR by 17
-estradiol (E2), with ARA70 being the most effective coactivator for conferring androgenic activity for E2 (6,55,57). In addition, ARA70 can function as a coactivator of AR in the presence of androst-5-ene-3,17-diol (Adiol), a precursor to testosterone. The activation is Adiol dependent and is not related to its metabolism to testosterone (57).
The use of a two-hybrid assay in mammalian cells has demonstrated that the antiandrogens hydroxyflutamide, bicalutamide, cyproterone acetate, and RU58841 can promote the interaction between AR and ARA70 in a dose-dependent manner, substantially enhancing AR transcriptional activity (58). ARA55 also enhances AR transcriptional activity in the presence of hydroxyflutamide (55). Thus, one way for progression to androgen-refractory prostate cancer to occur may be through an increase in coactivator RNA or protein levels or mutations in coactivators that provide a means for antiandrogens to activate the AR.
Another way for androgen-refractory prostate cancer formation to occur may be by the recruitment of coactivators that alter the steroid specificity of mutant AR activation. For example, ARA54, in conjunction with the T877A mutant AR found in the LNCaP cell line, is able to enhance transcriptional activity of the AR in the presence of both E2 and hydroxyflutamide (54). ARA54 does not have this effect with wild-type AR or with a different AR mutant (E708K), which is associated with partial androgen insensitivity syndrome but has not been documented to be related to androgen-refractory prostate cancer.
A final way for androgen-refractory prostate cancer formation to occur may be by AR coactivators, taking advantage of the adrenal androgens that remain available following hormone ablation therapy. Transfection of LNCaP cells with the proto-oncogene Her2/Neu induces PSA through the mitogen-activated protein kinase pathway at low androgen levels (59). Furthermore, AR-sensitive promoters are activated when ARA70 and the AR are expressed in conjunction with the overexpression of the Her2/Neu proto-oncogene (59). The mechanism by which the interaction increases AR activity is not clear, but it may provide a novel pathway for AR transactivation with low levels of androgens.
Thus, given current knowledge, there are several possible ways by which AR coactivators may be involved in the progression of androgen-sensitive prostate cancer to androgen-refractory prostate cancer. First, overexpression of certain coactivators may cause activation of AR by nonandrogenic steroids. Second, overexpression of other coactivators may cause activation of the AR by antiandrogens. Third, AR mutations may result in conformational changes of the AR that, in combination with certain coactivators, can result in activation of the AR. These three mechanisms, alone or in combination, may provide a means for prostate cancer cells to overcome their initial dependence on androgens. However, there is as yet no direct evidence of altered expression levels of the coactivators or of altered interactions between the coactivators and AR in androgen-refractory prostate cancer.
Activation of the AR by Peptide Growth Factors and Cytokines
The AR exists as a phosphoprotein, and the functional status of the AR is associated with its phosphorylation status (60). Induction of AR transcriptional activity by the factors that mediate AR phosphorylation may provide one mechanism for progression to androgen-refractory prostate cancer. These factors include peptide growth factors and cytokines. For example, serum levels of insulin-like growth factor-I (IGF-I) have been reported to be associated with prostate cancer risk, although whether elevated levels of IGF-I are associated with androgen-refractory prostate cancer has not been determined (61). Blockade of IGF-I signaling, by reduced expression of its cognate receptor, inhibits growth of prostate cancer cells in vitro and in vivo (62,63). Transgenic mice expressing IGF-I in prostate epithelium exhibit activation of IGF-I receptor and spontaneous tumorigenesis in the prostate (64). In the absence of androgen, IGF-I is also able to promote AR transcriptional activity in vitro (65). In addition, the antiandrogen bicalutamide can inhibit the activation of the AR by nonsteroidal factors such as IGF-I (65), which suggests that this activation requires the AR. Taken together, these results suggest that IGF-I may play a role in the progression from androgen-sensitive to androgen-refractory prostate cancer in a manner that is independent of androgen. That the wild-type AR can be activated by IGF-I (65) indicates that the activation of the AR by IGF-I may be mediated through the signaling cascade initiated from ligand binding of the IGF-I receptor rather than through mutations in the AR itself.
Other peptide growth factors, such as keratinocyte growth factor and epidermal growth factor, can also stimulate the transcription-promoting activity of the AR (65). That is, each of these growth factors can activate transcriptional activity from androgen-responsive reporter gene constructs, either in the absence of androgen or synergistically, in conjunction with androgens. Other nonsteroidal molecules, including cytokines, such as interleukin 6 (IL-6), and activating factors of protein kinase A (PKA), such as 8-Br-cAMP or forskolin, can also activate the AR pathway (Fig. 1). Forskolin activates the AR through a PKA-signaling pathway by way of adenylate cyclase to increase intracellular levels of cAMP (66–69). IL-6 not only activates AR-responsive reporter gene constructs in DU-145 prostate cancer cells but also increases PSA secretion by LNCaP cells (70). Clinical data show that serum IL-6 levels are elevated in men with hormone-refractory prostate cancer and that these high serum IL-6 levels are accompanied by high levels of serum PSA (71–73). However, the clinical importance of elevated serum levels of IL-6 in patients with androgen-refractory prostate cancer is unclear.
|
Growth factors serve as ligands for receptor tyrosine kinases and activate downstream intracellular kinase cascades. Receptor tyrosine kinases may also be involved in the progression to androgen-refractory prostate cancer through an interaction with the AR. The receptor tyrosine kinase Her2/Neu (also know as erbB2) is expressed at low levels in normal secretory epithelial cells, including prostate epithelial cells (74,75). Although the clinical importance of Her2/Neu in prostate cancer is not yet known, several studies (76–79) have demonstrated Her2/Neu protein overexpression and/or gene amplification in a subset of prostate cancer patients. Overexpression of Her2/Neu not only stimulates proliferation of LNCaP cells but also enhances AR-transactivating activity both in the absence of androgens and in the presence of androgens, in which case activation is synergistic (59,80). Moreover, Her2/Neu induces PSA expression, and this induction can be partially inhibited by blocking the MAP kinase pathway (59). Thus, MAP kinase may mediate the activation of the AR by Her2/Neu. In addition, protein kinase inhibitors can affect androgen-induced transcriptional activity of the AR (68,70).
Because Her2/Neu is a critical component of IL-6 signaling through the MAP kinase pathway in prostate cancer cells (81), it is possible that signaling pathways involving the transcriptional activity of the AR by both IL-6 and Her2/Neu may be merged through the MAP kinase cascade (Fig. 1
). This hypothesis is supported by the following findings: 1) Activation of the AR by either IL-6 or Her2/Neu can be attenuated, but not completely blocked, by the antiandrogens bicalutamide or hydroxyflutamide (59,70,80); 2) stimulation of PSA secretion by IL-6 or activation of the AR by Her2/Neu can be inhibited by the MAP kinase inhibitor PD98059 (59,70); and 3) one MAP kinase, MAP kinase kinase kinase 1, can induce the promoter activity of an AR-regulated gene in both an AR-dependent and an androgen-independent manner (82).
The AR, in addition to being activated by peptide growth factors, cytokines, and receptor tyrosine kinases, can be regulated by many other nonsteroidal factors, including -catenin, caveolin-1, histone acetyltransferase binding to the origin replication complex, cyclin E, tumor susceptibility gene TSG 101, butyrate, and Smad3 (83–92). Thus, it appears that AR-mediated transcriptional activities can be affected in many ways at multiple levels. However, because the results that show nonsteroidal activation of the AR are all from in vitro studies, it is important for future studies to determine the clinical importance of these findings with reference to androgen-refractory prostate cancer patients.
Progression to Androgen-Refractory Prostate Cancer Via Bypassing the AR Pathway
Even though the AR plays a major role in the progression to androgen-refractory prostate cancer, androgen-refractory prostate cancer cells may use other pathways for proliferation via bypassing the AR entirely. One potentially relevant pathway is NE differentiation in prostate tumors. The prevalence of focal NE cells in prostate adenocarcinoma varies from 30% to 100%, depending on the sources of tumor samples and the methods used to detect NE cells. NE cells, which become more prevalent after long-term antiandrogen therapy both in vitro and in vivo (93), are nonmitotic and do not express the AR. The absence of proliferation may make NE cells relatively resistant to radiation therapy and endocrine therapy (94). The prevalence of proliferating carcinoma in the vicinity of NE cells (95,96) suggests that these cells may play a role in the growth of androgen-refractory prostate cancer. NE cells may contribute to the progression to androgen-refractory prostate cancer via their production of neurosecretory products, such as parathyroid hormone-related protein, the neurotransmitter serotonin, the neuropeptide hormone bombesin, calcitonin, chromagranin A, neurotensin, and thyroid-stimulatory hormone (97–100).
Although the mechanism of NE differentiation after androgen ablation is not completely understood, recent studies (101,102) show that IL-6 treatment induces LNCaP and PC-3 cells to undergo NE differentiation. The process of NE differentiation induced by IL-6 in LNCaP cells is accompanied by the activation, through phosphatidylinositol 3 kinase (PI3K), of the nonreceptor tyrosine kinase Etk/Bmx; IL-6-induced NE differentiation can be blocked by a dominant-negative mutant form of Etk. IL-6 can also activate signal transducer and activators of transcription (STATs), such as STAT3, through the Janus kinase pathway. STAT3, one of the downstream targets of Etk (103), mediates the process of IL-6-induced NE differentiation in LNCaP and PC-3 cells (104) (Fig. 2). Therefore, IL-6 may induce NE differentiation in prostate cancer cell lines by activating phosphatidylinositol 3-kinase (PI3K) (105), Etk, and STAT3 (Fig. 2).
|
B in prostate cancer cell lines. Establishment of an IL-6 autocrine loop after androgen ablation in prostate tumors is likely mediated by loss of repression of NFAlthough no in vivo data are available to account for the enrichment in NE cells after androgen ablation therapy, circulating levels of IL-6 are elevated in patients with hormone-refractory disease (71). It is possible that the high levels of serum IL-6 activate the PI3K–Etk–STAT3 signaling cascade to cause NE differentiation in prostate tumors.
Androgen-refractory prostate cancer cells may utilize other cellular pathways for their survival. Androgen withdrawal triggers apoptosis in both normal and malignant androgen-dependent prostate epithelial cells. However, androgen-refractory prostate cancer cells do not undergo apoptosis (10). Therefore, activation of antiapoptotic signaling pathways, such as the PI3 kinase and related pathways, should be critical for the survival of androgen-refractory prostate cancer cells. PI3K is activated by a number of survival factors, such as IL-6, and by factors that activate Her-2/Neu (Fig. 3). PI3K phosphorylates phosphatidylinositol to generate D-3 phosphatidylinositol, including phosphatidylinositol-3,4,5-triphosphate and phosphatidylinositol 3,4-bisphosphate, both of which participate in the activation of the downstream target, protein kinase B (PKB, also known as Akt). PKB is one of the key regulatory molecules involved in the protection of cells against apoptosis (106,107). PTEN (also known as MMAC1 and TEP1) has lipid phosphatase activity that metabolizes PIP3 (phosphatidylinositol triphosphate) (108–112). Ultimately, PTEN functions as a tumor suppressor primarily through negative regulation of the PI3K/Akt pathway (113–115).
|
PTEN is inactivated in several types of cancers, including those from prostate, brain, breast, endometrium, and kidney (116). Loss of PTEN function in prostate cancer can occur through a variety of mechanisms, including deletion, mutation, and, in a xenograft model, methylation (108,117–119). Although the frequency of PTEN mutations in prostate cancer is relatively low overall, inactivation of PTEN is more frequent in advanced stages of the tumor (117,120,121). Thus, loss of PTEN function may favor tumor cells surviving the selective pressure caused by androgen ablation therapy. In addition, one recent study (122) has demonstrated that PTEN functions as an antagonist to block AR signaling. These data suggest that loss of PTEN may also have a direct impact on androgen-independent activation of the AR.
Loss of PTEN and activation of PKB/Akt in prostate cancer cells might provide a favorable cellular environment for Bcl-2 and Bcl-XL proteins to function as inhibitors of apoptosis. PKB/Akt phosphorylates Bad, a proapoptotic member of the Bcl-2 family that, when dephosphorylated, displaces Bax from binding to Bcl-2 and Bcl-XL, resulting in cell death (107). Bad phosphorylation frees Bcl-2 and Bcl-XL, allowing them to act as antiapoptotic proteins. In the normal prostate, Bcl-2 is expressed in the basal epithelial cells but not in the luminal epithelial cells (123,124). Overexpression of Bcl-2 has been implicated in the conversion of androgen-dependent to androgen-refractory lesions (125–127). Bcl-2 is overexpressed in early-stage disease, but most studies have shown higher frequencies of overexpression in advanced prostate cancer (126). These in vivo observations are further supported by in vitro studies that show that forced expression of Bcl-2 in LNCaP cells protects cells from apoptosis caused by androgen withdrawal and enables cells to be less dependent on androgens (127). Bcl-2 may also affect the function of the AR through alteration of the subcellular distribution of the AR in prostate cancer cells (128). Thus, inactivation of Bad or expression of Bcl-2 may confer on prostate cancer cells the ability to avoid apoptosis, which is the primary consequence of androgen ablation therapy, thus enabling androgen-sensitive prostate cancer to progress to androgen-refractory prostate cancer.
|
CONCLUSION |
|---|
|
TopAbstractIntroductionAndrogens and the Androgen...Prostate Cancer Progression and...Mechanisms for Progression to...ConclusionReferences |
|---|
A number of mechanisms have been identified that may contribute to the progression of prostate cancer from androgen sensitive to androgen refractory. Two mechanisms alter the AR directly, modulating its ability to respond to specific ligands. First, mutations in the AR hormone-binding domain or amplification of the AR gene could result in an increased sensitivity to adrenal androgens. Second, mutations in several portions of the AR could allow it to respond to other steroids or antiandrogens. Both mechanisms are probably responsible for some cases of androgen-refractory prostate cancer, but it is apparent from current clinical research that they are responsible for only a minority of such cases.
AR signaling may also be modulated by three indirect mechanisms. In one such mechanism, coactivators could augment the sensitivity of the AR to androgens and even other nonandrogenic compounds. Although these coactivators have yet to be linked directly to androgen-refractory prostate cancer, it seems likely that this could be an important pathway to androgen-refractory prostate cancer because of the large number of coactivators that have already been identified. In a second indirect mechanism, AR signaling may be enhanced through activation of the AR by peptide growth factors and cytokines. In a third indirect mechanism, prostate cancer may become androgen refractory if the AR is bypassed. This mechanism could reflect inactivation of PTEN or the development of alternative pathways for growth. These three indirect mechanisms are likely to be involved in the majority of cases of androgen-refractory prostate cancer because they do not require mutated or amplified AR but could result from mutation or altered expression of a large number of different genes. However, although each of these mechanisms may not involve classical AR signaling, the fact that the AR is expressed in androgen-refractory prostate cancer cells indicates that it remains an important component of such cells. Therefore, the AR must be necessary for and able to modulate some signaling pathways in the absence of its ligand.
In conclusion, many different mechanisms are emerging that may be involved in the progression of androgen-sensitive to androgen-refractory prostate cancer. This finding is not surprising, given the heterogeneous nature of prostate cancer and the large number of interconnected pathways in which the AR is involved. However, the key genes and pathways that are regulated by AR have not yet been defined clearly. It will be important to elucidate how the interconnected pathways downstream and upstream of AR contribute to the growth and maintenance of the normal prostatic cells. Once the mechanisms of progression to androgen-refractory prostate cancer are better understood, it may be possible to design rational strategies for the treatment and possible cure of both androgen-sensitive and androgen-refractory prostate cancer.
|
REFERENCES |
|---|
|
TopAbstractIntroductionAndrogens and the Androgen...Prostate Cancer Progression and...Mechanisms for Progression to...ConclusionReferences |
|---|
1 Gittes RF. Carcinoma of the prostate. N Engl J Med 1991;324:236–45.[Web of Science][Medline]
2 Dawson NA, Vogelzang NJ. Prostate cancer. New York (NY): Wiley-Liss; 1994.
3 Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin 2000;50:7–33.[Abstract]
4 Lindzey J, Kumar MV, Grossmann M, Young C, Tindall DJ. Molecular mechanisms of androgen action. Vitam Horm 1994;49:383–432.[Web of Science][Medline]
5 MacLean HE, Warne GL, Zajac JD. Localization of functional domains in the androgen receptor. J Steroid Biochem Mol Biol 1997;62:233–42.[CrossRef][Web of Science][Medline]
6 Yeh S, Chang HC, Miyamoto H, Takatera H, Rahman M, Kang HY, et al. Differential induction of the androgen receptor transcriptional activity by selective androgen receptor coactivators. Keio J Med 1999;48:87–92.[Medline]
7 Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70.[CrossRef][Web of Science][Medline]
8
Russell PJ, Bennett S, Stricker P. Growth factor involvement in progression of prostate cancer. Clin Chem 1998;44:705–23.
9 Bostwick DG, MacLennan GT, Larson TR. Prostate cancer: what every man—and his family—needs to know. New York (NY): The American Cancer Society-Villard Books; 1999.
10 Denmeade SR, Lin XS, Isaacs JT. Role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer [published erratum appears in Prostate 1996;28:414]. Prostate 1996;28:251–65.[CrossRef][Web of Science][Medline]
11 van der Kwast TH, Tetu B. Androgen receptors in untreated and treated prostatic intraepithelial neoplasia. Eur Urol 1996;30:265–8.[Web of Science][Medline]
12 Sadi MV, Walsh PC, Barrack ER. Immunohistochemical study of androgen receptors in metastatic prostate cancer. Comparison of receptor content and response to hormonal therapy. Cancer 1991;67:3057–64.[CrossRef][Web of Science][Medline]
13
Tilley WD, Lim-Tio SS, Horsfall DJ, Aspinall JO, Marshall VR, Skinner JM. Detection of discrete androgen receptor epitopes in prostate cancer by immunostaining: measurement by color video image analysis. Cancer Res 1994;54:4096–102.
14 Hobisch A, Culig Z, Radmayr C, Bartsch G, Klocker H, Hittmair A. Androgen receptor status of lymph node metastases from prostate cancer. Prostate 1996;28:129–35.[CrossRef][Web of Science][Medline]
15 van der Kwast TH, Schalken J, Ruizeveld de Winter JA, van Vroonhoven CC, Mulder E, Boersma W, et al. Androgen receptors in endocrine-therapy-resistant human prostate cancer. Int J Cancer 1991;48:189–93.[Web of Science][Medline]
16
Hobisch A, Culig Z, Radmayr C, Bartsch G, Klocker H, Hittmair A. Distant metastases from prostatic carcinoma express androgen receptor protein. Cancer Res 1995;55:3068–72.
17
Thalmann GN, Anezinis PE, Chang SM, Zhau HE, Kim EE, Hopwood VL, et al. Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer [published erratum appears in Cancer Res 1994;54:3953]. Cancer Res 1994;54:2577–81.
18
Kokontis J, Takakura K, Hay N, Liao S. Increased androgen receptor activity and altered c-myc expression in prostate cancer cells after long-term androgen deprivation. Cancer Res 1994;54:1566–73.
19
Kokontis JM, Hay N, Liao S. Progression of LNCaP prostate tumor cells during androgen deprivation: hormone-independent growth, repression of proliferation by androgen, and role for p27Kip1 in androgen-induced cell cycle arrest. Mol Endocrinol 1998;12:941–53.
20
Nagabhushan M, Miller CM, Pretlow TP, Giaconia JM, Edgehouse NL, Schwartz S, et al. CWR22: the first human prostate cancer xenograft with strongly androgen-dependent and relapsed strains both in vivo and in soft agar. Cancer Res 1996;56:3042–6.
21 Klein KA, Reiter RE, Redula J, Moradi H, Zhu XL, Brothman AR, et al. Progression of metastatic human prostate cancer to androgen independence in immunodeficient SCID mice. Nat Med 1997;3:402–8.[CrossRef][Web of Science][Medline]
22
Craft N, Chhor C, Tran C, Belldegrun A, DeKernion J, Witte ON, et al. Evidence for clonal outgrowth of androgen-independent prostate cancer cells from androgen-dependent tumors through a two-step process. Cancer Res 1999;59:5030–6.
23
Isaacs JT, Heston WD, Weissman RM, Coffey DS. Animal models of the hormone-sensitive and -insensitive prostatic adenocarcinomas, Dunning R-3327-H, R-3327-HI, and R-3327-AT. Cancer Res 1978;38:4353–9.
24
Gingrich JR, Barrios RJ, Kattan MW, Nahm HS, Finegold MJ, Greenberg NM. Androgen-independent prostate cancer progression in the TRAMP model. Cancer Res 1997;57:4687–91.
25 Kasper S, Sheppard PC, Yan Y, Pettigrew N, Borowsky AD, Prins GS, et al. Development, progression, and androgen-dependence of prostate tumors in probasin-large T antigen transgenic mice: a model for prostate cancer [corrected and republished article originally printed in Lab Invest 1998;78:319–33]. Lab Invest 1998;78:i–xv.[Web of Science][Medline]
26 Green JE, Greenberg NM, Ashendel CL, Barrett JC, Boone C, Getzenberg RH, et al. Workgroup 3: transgenic and reconstitution models of prostate cancer. Prostate 1998;36:59–63.[CrossRef][Web of Science][Medline]
27
Bubendorf L, Kolmer M, Kononen J, Koivisto P, Mousses S, Chen Y, et al. Hormone therapy failure in human prostate cancer: analysis by complementary DNA and tissue microarrays. J Natl Cancer Inst 1999;91:1758–64.
28 Koivisto P, Kolmer M, Visakorpi T, Kallioniemi OP. Androgen receptor gene and hormonal therapy failure of prostate cancer. Am J Pathol 1998;152:1–9.[Abstract]
29
Tan J, Sharief Y, Hamil KG, Gregory CW, Zang DY, Sar M, et al. Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol Endocrinol 1997;11:450–9.
30
Taplin ME, Bubley GJ, Shuster TD, Frantz ME, Spooner AE, Ogata GK, et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med 1995;332:1393–8.
31 Fenton MA, Shuster TD, Fertig AM, Taplin ME, Kolvenbag G, Bubley GJ, et al. Functional characterization of mutant androgen receptors from androgen-independent prostate cancer. Clin Cancer Res 1997;3:1383–8.[Abstract]
32 Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinanen R, Palmberg C, et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 1995;9:401–6.[CrossRef][Web of Science][Medline]
33
Koivisto P, Kononen J, Palmberg C, Tammela T, Hyytinen E, Isola J, et al. Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res 1997;57:314–9.
34 Palmberg C, Koivisto P, Hyytinen E, Isola J, Visakorpi T, Kallioniemi OP, et al. Androgen receptor gene amplification in a recurrent prostate cancer after monotherapy with the nonsteroidal potent antiandrogen Casodex (bicalutamide) with a subsequent favorable response to maximal androgen blockade. Eur Urol 1997;31:216–9.[Web of Science][Medline]
35
Koivisto PA, Schleutker J, Helin H, Ehren-van Eekelen C, Kallioniemi OP, Trapman J. Androgen receptor gene alterations and chromosomal gains and losses in prostate carcinomas appearing during finasteride treatment for benign prostatic hyperplasia. Clin Cancer Res 1999;5:3578–82.
36
Bubendorf L, Kononen J, Koivisto P, Schraml P, Moch H, Gasser TC, et al. Survey of gene amplifications during prostate cancer progression by high-throughout fluorescence in situ hybridization on tissue microarrays. Cancer Res 1999;59:803–6.
37 Koivisto P, Visakorpi T, Kallioniemi OP. Androgen receptor gene amplification: a novel molecular mechanism for endocrine therapy resistance in human prostate cancer. Scand J Clin Lab Invest Suppl 1996;226:57–63.[Medline]
38 Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma [published erratum appears in N Engl J Med 1989;321:1420]. N Engl J Med 1989;321:419–24.[Abstract]
39 Prostate Cancer Trialists' Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. Lancet 1995;346:265–9.[Web of Science][Medline]
40 Koivisto PA, Rantala I. Amplification of the androgen receptor gene is associated with P53 mutation in hormone-refractory recurrent prostate cancer. J Pathol 1999;187:237–41.[CrossRef][Web of Science][Medline]
41 Akimoto S. Antiandrogen withdrawal syndrome. Nippon Rinsho 1998;56:2135–9.[Medline]
42 Kelly WK. Endocrine withdrawal syndrome and its relevance to the management of hormone refractory prostate cancer. Eur Urol 1998;34 Suppl 3:18–23.
43 Middleman MN, Lush RM, Figg WD. The mutated androgen receptor and its implications for the treatment of metastatic carcinoma of the prostate. Pharmacotherapy 1996;16:376–81.[Web of Science][Medline]
44 Wirth MP, Froschermaier SE. The antiandrogen withdrawal syndrome. Urol Res 1997;25 Suppl 2:S67–71.
45 Longmore L, Foley JP, Rozanski TA, Higgins B, Thompson M. Prolonged prostate-specific antigen response in flutamide withdrawal syndrome despite disease progression. South Med J 1998;91:573–5.[Web of Science][Medline]
46 Gottlieb B, Beitel LK, Lumbroso R, Pinsky L, Trifiro M. Update of the androgen receptor gene mutations database. Hum Mutat 1999;14:103–14.[CrossRef][Web of Science][Medline]
47 Suzuki H, Akakura K, Komiya A, Aida S, Akimoto S, Shimazaki J. Codon 877 mutation in the androgen receptor gene in advanced prostate cancer: relation to antiandrogen withdrawal syndrome. Prostate 1996;29:153–8.[CrossRef][Web of Science][Medline]
48
Taplin M, Bubley GJ, Ko YJ, Small EJ, Upton M, Rajeshkumar B, et al. Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res 1999;59:2511–5.
49 Veldscholte J, Ris-Stalpers C, Kuiper G, Jenster GG, Berrevoets C, Claassen E, et al. A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem Biophys Res Commun 1990;172:534–40.
50
Chen D, Ma H, Hong H, Koh SS, Huang SM, Schurter BT, et al. Regulation of transcription by a protein methyltransferase. Science 1999;284:2174–7.
51
Ma H, Hong H, Huang SM, Irvine RA, Webb P, Kushner PJ, et al. Multiple signal input and output domains of the 160-kilodalton nuclear receptor coactivator proteins. Mol Cell Biol 1999;19:6164–73.
52
Alen P, Claessens F, Verhoeven G, Rombauts W, Peeters B. The androgen receptor amino-terminal domain plays a key role in p160 coactivator-stimulated gene transcription. Mol Cell Biol 1999;19:6085–97.
53
Park J, Irvine R, Buchanan G, Koh SS, Park JM, Tilley WD, et al. Breast cancer susceptibility gene 1 (BRCA1) is a coactivator of the androgen receptor. Cancer Res 2000;60:5946–9.
54
Kang HY, Yeh S, Fujimoto N, Chang C. Cloning and characterization of androgen receptor coactivator ARA54, a novel protein that associates with the androgen receptor. J Biol Chem 1999;274:8570–6.
55
Fujimoto N, Yeh S, Kang HY, Inui S, Chang HC, Mizokami A, et al. Cloning and characterization of androgen receptor coactivator, ARA55, in human prostate. J Biol Chem 1999;274:8316–21.
56
Miyamoto H, Yeh S, Wilding G, Chang C. Promotion of agonist activity of antiandrogens by the androgen receptor coactivator, ARA70, in human prostate cancer DU145 cells. Proc Natl Acad Sci U S A 1998;95:7379–84.
57
Miyamoto H, Yeh S, Lardy H, Messing E, Chang C. Delta5-androstenediol is a natural hormone with androgenic activity in human prostate cancer cells. Proc Natl Acad Sci U S A 1998;95:11083–8.
58
Yeh S, Chang C. Cloning and characterization of a specific coactivator, ARA70, for the androgen receptor in human prostate cells. Proc Natl Acad Sci U S A 1996;93:5517–21.
59
Yeh S, Lin HK, Kang HY, Thin TH, Lin MF, Chang C. From HER2/Neu signal cascade to androgen receptor and its coactivators: a novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells. Proc Natl Acad Sci U S A 1999;96:5458–63.
60 Wang LG, Liu XM, Kreis W, Budman DR. Phosphorylation/dephosphorylation of androgen receptor as a determinant of androgen agonistic or antagonistic activity. Biochem Biophys Res Comm 1999;259:21–8.[CrossRef][Web of Science][Medline]
61
Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 1998;279:563–6.
62
Burfeind P, Chernicky CL, Rininsland F, Ilan J, Ilan J. Antisense RNA to the type I insulin-like growth factor receptor suppresses tumor growth and prevents invasion by rat prostate cancer cells in vivo. Proc Natl Acad Sci U S A 1996;93:7263–8.
63
Lamharzi N, Schally AV, Koppan M, Groot K. Growth hormone-releasing hormone antagonist MZ-5–156 inhibits growth of DU-145 human androgen-independent prostate carcinoma in nude mice and suppresses the levels and mRNA expression of insulin-like growth factor II in tumors. Proc Natl Acad Sci U S A 1998;95:8864–8.
64
DiGiovanni J, Kiguchi K, Frijhoff A, Wilker E, Bol DK, Beltran L, et al. Deregulated expression of insulin-like growth factor 1 in prostate epithelium leads to neoplasia in transgenic mice. Proc Natl Acad Sci U S A 2000;97:3455–60.
65
Culig Z, Hobisch A, Cronauer MV, Radmayr C, Trapman J, Hittmair A, et al. Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res 1994;54:5474–8.
66 Ikonen T, Palvimo JJ, Kallio PJ, Reinikainen P, Janne OA. Stimulation of androgen-regulated transactivation by modulators of protein phosphorylation. Endocrinology 1994;135:1359–66.[Abstract]
67 Ding VD, Moller DE, Feeney WP, Didolkar V, Nakhla AM, Rhodes L, et al. Sex hormong-binding globulin mediates prostate androgen receptor action via a novel signaling pathway. Endoocrinology 1998;139:213–8.
68
Nazareth LV, Weigel NL. Activation of the human androgen receptor through a protein kinase A signaling pathway. J Biol Chem 1996;271:19900–7.
69
Sadar MD. Androgen-independent induction of prostate-specific antigen gene expression via cross-talk between the androgen receptor and protein kinase A signal transduction pathways. J Biol Chem 1999;274:7777–83.
70
Hobisch A, Eder IE, Putz T, Horninger W, Bartsch G, Klocker H, et al. Interleukin-6 regulates prostate-specific protein expression in prostate carcinoma cells by activation of the androgen receptor. Cancer Res 1998;58:4640–5.
71 Drachenberg DE, Elgamal AA, Rowbotham R, Peterson M, Murphy GP. Circulating levels of interleukin-6 in patients with hormone refractory prostate cancer. Prostate 1999;41:127–33.[CrossRef][Web of Science][Medline]
72 Adler HL, McCurdy MA, Kattan MW, Timme TL, Scardino PT, Thompson TC. Elevated levels of circulating interleukin-6 and transforming growth factor-beta1 in patients with metastatic prostatic carcinoma. J Urol 1999;161:182–7.[CrossRef][Web of Science][Medline]
73 Wise GJ, Marella VK, Talluri G, Shirazian D. Cytokine variations in patients with hormone treated prostate cancer. J Urol 2000;164:722–5.[CrossRef][Web of Science][Medline]
74 Ware JL, Maygarden SJ, Koontz WW Jr, Strom SC. Immunohistochemical detection of c-erbB-2 protein in human benign and neoplastic prostate. Hum Pathol 1991;22:254–8.[CrossRef][Web of Science][Medline]
75
Robinson D, He F, Pretlow T, Kung HJ. A tyrosine kinase profile of prostate carcinoma. Proc Natl Acad Sci U S A 1996;93:5958–62.
76 Mellon K, Thompson S, Charlton RG, Marsh C, Robinson M, Lane DP, et al. p53, c-erbB-2 and the epidermal growth factor receptor in the benign and malignant prostate. J Urol 1992;147:496–9.[Web of Science][Medline]
77 Kuhn EJ, Kurnot RA, Sesterhenn IA, Chang EH, Moul JW. Expression of the c-erbB-2 (HER-2/neu) oncoprotein in human prostatic carcinoma. J Urol 1993;150:1427–33.[Web of Science][Medline]
78
Myers RB, Srivastava S, Oelschlager DK, Grizzle WE. Expression of p160erbB-3 and p185erbB-2 in prostatic intraepithelial neoplasia and prostatic adenocarcinoma. J Natl Cancer Inst 1994;86:1140–5.
79 Ross JS, Sheehan C, Hayner-Buchan AM, Ambros RA, Kallakury BV, Kaufman R, et al. HER-2/neu gene amplification status in prostate cancer by fluorescence in situ hybridization. Hum Pathol 1997;28:827–33.[CrossRef][Web of Science][Medline]
80 Craft N, Shostak Y, Carey M, Sawyers CL. A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med 1999;5:280–5.[CrossRef][Web of Science][Medline]
81 Qiu Y, Ravi L, Kung HJ. Requirement of ErbB2 for signalling by interleukin-6 in prostate carcinoma cells. Nature 1998;393:83–5.[CrossRef][Medline]
82
Abreu-Martin MT, Chari A, Palladino AA, Craft NA, Sawyers CL. Mitogen-activated protein kinase kinase kinase 1 activates androgen receptor-dependent transcription and apoptosis in prostate cancer. Mol Cell Biol 1999;19:5143–54.
83
Truica CI, Byers S, Gelmann EP. Beta-catenin affects androgen receptor transcriptional activity and ligand specificity. Cancer Res 2000;60:4709–13.
84
Lu ML, Schneider MC, Zheng Y, Zhang X, Richie JP. Caveolin-1 interacts with androgen receptor. A positive modulator of androgen receptor mediated transactivation. J Biol Chem 2001;276:13442–51.
85
Sharma M, Zarnegar M, Li X, Lim B, Sun Z. Androgen receptor interacts with a novel MYST protein, HBO1. J Biol Chem 2000;275:35200–8.
86
Yamamoto A, Hashimoto Y, Kohri K, Ogata E, Kato S, Ikeda K, et al. Cyclin E as a coactivator of the androgen receptor. J Cell Biol 2000;150:873–80.
87 Watanabe M, Yanagi Y, Masuhiro Y, Yano T, Yoshikawa H, Yanagisawa J, et al. A putative tumor suppressor, TSG101, acts as a transcriptional suppressor through its coiled–coil domain. Biochem Biophys Res Commun 1998;245:900–5.[CrossRef][Web of Science][Medline]
88 Sun Z, Pan J, Hope WX, Cohen SN, Balk SP. Tumor susceptibility gene 101 protein represses androgen receptor transactivation and interacts with p300. Cancer 1999;86:689–96.[CrossRef][Web of Science][Medline]
89 Ulrix W, Swinnen JV, Heyns W, Verhoeven G. The differentiation-related gene 1, Drg1, is markedly upregulated by androgens in LNCaP prostatic adenocarcinoma cells. FEBS Lett 1999;455:23–6.[CrossRef][Web of Science][Medline]
90
Sadar MD, Gleave ME. Ligand-independent activation of the androgen receptor by the differentiation agent butyrate in human prostate cancer cells. Cancer Res 2000;60:5825–31.
91
Hayes SA, Zarnegar M, Sharma M, Yang F, Peehl DM, ten Dijke P, et al. SMAD3 represses androgen receptor-mediated transcription. Cancer Res 2001;61:2112–8.
92
Kang HY, Lin HK, Hu YC, Yeh S, Huang KE, Chang C. From transforming growth factor-beta signaling to androgen action: identification of Smad3 as an androgen receptor coregulator in prostate cancer cells. Proc Natl Acad Sci U S A 2001;98:3018–23.
93 Abrahamsson PA. Neuroendocrine differentiation in prostatic carcinoma. Prostate 1999;39:135–48.[CrossRef][Web of Science][Medline]
94 Bonkhoff H. Neuroendocrine cells in benign and malignant prostate tissue: morphogenesis, proliferation, and androgen receptor status. Prostate Suppl 1998;8:18–22.[Medline]
95 Bonkhoff H, Wernert N, Dhom G, Remberger K. Relation of endocrine–paracrine cells to cell proliferation in normal, hyperplastic, and neoplastic human prostate. Prostate 1991;19:91–8.[Web of Science][Medline]
96 Bonkhoff H, Stein U, Remberger K. Endocrine–paracrine cell types in the prostate and prostatic adenocarcinoma are postmitotic cells. Hum Pathol 1995;26:167–70.[CrossRef][Web of Science][Medline]
97 Seuwen K, Pouyssegur J. Serotonin as a growth factor. Biochem Pharmacol 1990;39:985–90.[CrossRef][Web of Science][Medline]
98 Willey JC, Lechner JF, Harris CC. Bombesin and the C-terminal tetradecapeptide of gastrin-releasing peptide are growth factors for normal human bronchial epithelial cells. Exp Cell Res 1984;153:245–8.[CrossRef][Web of Science][Medline]
99 Dalsgaard CJ, Hultgardh-Nilsson A, Haegerstrand A, Nilsson J. Neuropeptides as growth factors. Possible roles in human diseases. Regul Pept 1989;25:1–9.[CrossRef][Web of Science][Medline]
100 Iwamura M, Abrahamsson PA, Foss KA, Wu G, Cockett AT, Deftos LJ. Parathyroid hormone-related protein: a potential autocrine growth regulator in human prostate cancer cell lines. Urology 1994;43:675–9.[CrossRef][Web of Science][Medline]
101 Diaz M, Abdul M, Hoosein N. Modulation of neuroendocrine differentiation in prostate cancer by interleukin-1 and -2. Prostate Suppl 1998;8:32–6.[CrossRef][Medline]
102 Mori S, Murakami-Mori K, Bonavida B. Interleukin-6 induces G1 arrest through induction of p27(Kip1), a cyclin-dependent kinase inhibitor, and neuron-like morphology in LNCaP prostate tumor cells. Biochem Biophys Res Commun 1999;257:609–14.[CrossRef][Web of Science][Medline]
103
Tsai YT, Su YH, Fang SS, Huang TN, Qiu Y, Jou YS, et al. Etk, a Btk family tyrosine kinase, mediates cellular transformation by linking Src to STAT3 activation. Mol Cell Biol 2000;20:2043–54.
104 Spiotto MT, Chung TD. STAT3 mediates IL-6-induced neuroendocrine differentiation in prostate cancer cells. Prostate 2000;42:186–95.[CrossRef][Web of Science][Medline]
105
Qiu Y, Robinson D, Pretlow TG, Kung HJ. Etk/Bmx, a tyrosine kinase with a pleckstrin-homology domain, is an effector of phosphatidylinositol 3'kinase and is involved in interleukin 6-induced neuroendocrine differentiation of prostate cancer cells. Proc Natl Acad Sci U S A 1998;95:3644–9.
106 Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Cur Biol 1997;7:261–9.[CrossRef][Web of Science][Medline]
107
Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev 1999;13:2905–27.
108
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997;275:1943–7.
109 Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997;15:356–62.[CrossRef][Web of Science][Medline]
110
Myers MP, Stolarov JP, Eng C, Li J, Wang SI, Wigler MH, et al. P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci U S A 1997;94:9052–7.
111 Maehama T, Dixon JE. PTEN: a tumour suppressor that functions as a phospholipid phosphatase. Trends Cell Biol 1999;9:125–8.[CrossRef][Web of Science][Medline]
112
Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, et al. The lipid phosphatase activity of PTEN is critical for its tumor suppressor function. Proc Natl Acad Sci U S A 1998;95:13513–8.
113
Wu X, Senechal K, Neshat MS, Whang YE, Sawyers CL. The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci U S A 1998;95:15587–91.
114
Sun H, Lesche R, Li DM, Liliental J, Zhang H, Gao J, et al. PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci U S A 1999;96:6199–204.
115
Persad S, Attwell S, Gray V, Delcommenne M, Troussard A, Sanghera J, et al. Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cells. Proc Natl Acad Sci U S A 2000;97:3207–12.
116
Ali IU, Schriml LM, Dean M. Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. J Natl Cancer Inst 1999;91:1922–32.
117
Cairns P, Okami K, Halachmi S, Halachmi N, Esteller M, Herman JG, et al. Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res 1997;57:4997–5000.
118 Feilotter HE, Nagai MA, Boag AH, Eng C, Mulligan LM. Analysis of PTEN and the 10q23 region in primary prostate carcinomas. Oncogene 1998;16:1743–8.[CrossRef][Web of Science][Medline]
119
Whang YE, Wu X, Suzuki H, Reiter RE, Tran C, Vessella RL, et al. Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci U S A 1998;95:5246–50.
120
Suzuki H, Freije D, Nusskern DR, Okami K, Cairns P, Sidransky D, et al. Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues. Cancer Res 1998;58:204–9.
121
McMenamin ME, Soung P, Perera S, Kaplan I, Loda M, Sellers WR. Loss of PTEN expression in paraffin-embedded primary prostate cancer correlates with high Gleason score and advanced stage. Cancer Res 1999;59:4291–6.
122
Li P, Nicosia SV, Bai W. Antagonism between PTEN/MMAC1/TEP-1 and androgen receptor in growth and apoptosis of prostatic cancer cells. J Biol Chem 2001;276:20444–50.
123
Hockenbery DM, Zutter M, Hickey W, Nahm M, Korsmeyer SJ. BCL2 protein is topographically restricted in tissues characterized by apoptotic cell death. Proc Natl Acad Sci U S A 1991;88:6961–5.
124
McDonnell TJ, Troncoso P, Brisbay SM, Logothetis C, Chung LW, Hsieh JT, et al. Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res 1992;52:6940–4.
125
Colombel M, Olsson CA, Ng PY, Buttyan R. Hormone-regulated apoptosis results from reentry of differentiated prostate cells onto a defective cell cycle. Cancer Res 1992;52:4313–9.
126 Colombel M, Symmans F, Gil S, O'Toole KM, Chopin D, Benson M, et al. Detection of the apoptosis-suppressing oncoprotein bc1–2 in hormone-refractory human prostate cancers. Am J Pathol 1993;143:390–400.[Abstract]
127
Raffo AJ, Perlman H, Chen MW, Day ML, Streitman JS, Buttyan R. Overexpression of bcl-2 protects prostate cancer cells from apoptosis in vitro and confers resistance to androgen depletion in vivo. Cancer Res 1995;55:4438–45.
128 Chaudhary KS, Abel PD, Nightingale J, Stamp GW, Lalani EN. Bcl-2 alters ligand dependent subcellular distribution of androgen receptor in human prostatic cancer cells [abstract]. Proc Am Assoc Cancer Res 2000;91:A307.
Manuscript received January 24, 2001; revised September 13, 2001; accepted September 25, 2001.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  F. Tang, J. Kokontis, Y. Lin, S. Liao, A. Lin, and J. Xiang Androgen via p21 Inhibits Tumor Necrosis Factor {alpha}-induced JNK Activation and Apoptosis J. Biol. Chem., November 20, 2009; 284(47): 32353 - 32358. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Gan, S. Chen, Y. Wang, A. Watahiki, L. Bohrer, Z. Sun, Y. Wang, and H. Huang Inhibition of the Androgen Receptor as a Novel Mechanism of Taxol Chemotherapy in Prostate Cancer Cancer Res., November 1, 2009; 69(21): 8386 - 8394. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. B. Dorff, C. M. Tangen, E. D. Crawford, D. P. Petrylak, C. S. Higano, D. Raghavan, D. I. Quinn, N. J. Vogelzang, and I. M. Thompson Review: Cooperative group trials -- Southwest Oncology Group (SWOG) innovations in advanced prostate cancer Therapeutic Advances in Medical Oncology, September 1, 2009; 1(2): 69 - 77. [Abstract] [PDF]
|
|
|
|
 |
|
 R. R. Chhipa, K.-S. Lee, S. Onate, Y. Wu, and C. Ip Prx1 Enhances Androgen Receptor Function in Prostate Cancer Cells by Increasing Receptor Affinity to Dihydrotestosterone Mol. Cancer Res., September 1, 2009; 7(9): 1543 - 1552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. TAKAHARA, H. AZUMA, T. SAKAMOTO, S. KIYAMA, T. INAMOTO, N. IBUKI, T. NISHIDA, H. NOMI, T. UBAI, N. SEGAWA, et al. Conversion of Prostate Cancer from Hormone Independency to Dependency Due to AMACR Inhibition: Involvement of Increased AR Expression and Decreased IGF1 Expression Anticancer Res, July 1, 2009; 29(7): 2497 - 2505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Lakshmikanthan, L. Zou, J. I. Kim, A. Michal, Z. Nie, N. C. Messias, J. L. Benovic, and Y. Daaka Identification of {beta}Arrestin2 as a corepressor of androgen receptor signaling in prostate cancer PNAS, June 9, 2009; 106(23): 9379 - 9384. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. V. Heemers, K. M. Regan, L. J. Schmidt, S. K. Anderson, K. V. Ballman, and D. J. Tindall Androgen Modulation of Coregulator Expression in Prostate Cancer Cells Mol. Endocrinol., April 1, 2009; 23(4): 572 - 583. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. K. Mukhopadhyay, J. Kim, B. Cinar, A. Ramachandran, M. H. Hager, D. Di Vizio, R. M. Adam, M. A. Rubin, P. Raychaudhuri, A. De Benedetti, et al. Heterogeneous Nuclear Ribonucleoprotein K Is a Novel Regulator of Androgen Receptor Translation Cancer Res., March 15, 2009; 69(6): 2210 - 2218. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Alam, M. Rajendran, S. Ouyang, S. Veeramani, L. Zhang, and M.-F. Lin A novel role of Shc adaptor proteins in steroid hormone-regulated cancers Endocr. Relat. Cancer, March 1, 2009; 16(1): 1 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-L. Zhu and N. Kyprianou Androgen receptor and growth factor signaling cross-talk in prostate cancer cells Endocr. Relat. Cancer, December 1, 2008; 15(4): 841 - 849. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Basak, D. Pookot, E. J. Noonan, and R. Dahiya Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function Mol. Cancer Ther., October 1, 2008; 7(10): 3195 - 3202. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Vasaitis, A. Belosay, A. Schayowitz, A. Khandelwal, P. Chopra, L. K. Gediya, Z. Guo, H.-B. Fang, V. C.O. Njar, and A. M.H. Brodie Androgen receptor inactivation contributes to antitumor efficacy of 17{alpha}-hydroxylase/17,20-lyase inhibitor 3{beta}-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene in prostate cancer Mol. Cancer Ther., August 1, 2008; 7(8): 2348 - 2357. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. A. Fritz, T.-M. Lin, and R. E. Peterson The aryl hydrocarbon receptor (AhR) inhibits vanadate-induced vascular endothelial growth factor (VEGF) production in TRAMP prostates Carcinogenesis, May 1, 2008; 29(5): 1077 - 1082. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. G. Wang, E. M. Johnson, Y. Kinoshita, J. S. Babb, M. T. Buckley, L. F. Liebes, J. Melamed, X.-M. Liu, R. Kurek, L. Ossowski, et al. Androgen Receptor Overexpression in Prostate Cancer Linked to Pur{alpha} Loss from a Novel Repressor Complex Cancer Res., April 15, 2008; 68(8): 2678 - 2688. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-L. Lin, A. Chiang, D. Chang, and S.-Y. Ying Loss of mir-146a function in hormone-refractory prostate cancer RNA, March 1, 2008; 14(3): 417 - 424. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. S. Lyons, S. Rao, W. Balkan, J. Faysal, C. A. Maiorino, and K. L. Burnstein Ligand-Independent Activation of Androgen Receptors by Rho GTPase Signaling in Prostate Cancer Mol. Endocrinol., March 1, 2008; 22(3): 597 - 608. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hara, H. Miyazaki, A. Lee, C. P. Tran, and R. E. Reiter Androgen Receptor and Invasion in Prostate Cancer Cancer Res., February 15, 2008; 68(4): 1128 - 1135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-L. Lin, D. Chang, A. Chiang, and S.-Y. Ying Androgen receptor regulates CD168 expression and signaling in prostate cancer Carcinogenesis, February 1, 2008; 29(2): 282 - 290. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Sterbis, C. Gao, B. Furusato, Y. Chen, S. Shaheduzzaman, L. Ravindranath, D. J. Osborn, I. L. Rosner, A. Dobi, D. G. McLeod, et al. Higher Expression of the Androgen-Regulated Gene PSA/HK3 mRNA in Prostate Cancer Tissues Predicts Biochemical Recurrence-Free Survival Clin. Cancer Res., February 1, 2008; 14(3): 758 - 763. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Neuwirt, M. Puhr, I. T Cavarretta, M. Mitterberger, A. Hobisch, and Z. Culig Suppressor of cytokine signalling-3 is up-regulated by androgen in prostate cancer cell lines and inhibits androgen-mediated proliferation and secretion Endocr. Relat. Cancer, December 1, 2007; 14(4): 1007 - 1019. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. V. Heemers and D. J. Tindall Androgen Receptor (AR) Coregulators: A Diversity of Functions Converging on and Regulating the AR Transcriptional Complex Endocr. Rev., December 1, 2007; 28(7): 778 - 808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Dehm and D. J. Tindall Androgen Receptor Structural and Functional Elements: Role and Regulation in Prostate Cancer Mol. Endocrinol., December 1, 2007; 21(12): 2855 - 2863. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. V. Heemers, K. M. Regan, S. M. Dehm, and D. J. Tindall Androgen Induction of the Androgen Receptor Coactivator Four and a Half LIM Domain Protein-2: Evidence for a Role for Serum Response Factor in Prostate Cancer Cancer Res., November 1, 2007; 67(21): 10592 - 10599. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Lapointe, C. Li, C. P. Giacomini, K. Salari, S. Huang, P. Wang, M. Ferrari, T. Hernandez-Boussard, J. D. Brooks, and J. R. Pollack Genomic Profiling Reveals Alternative Genetic Pathways of Prostate Tumorigenesis Cancer Res., September 15, 2007; 67(18): 8504 - 8510. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S Darby, J Stockley, M M Khan, C N Robson, H Y Leung, and V J Gnanapragasam Expression of GnRH type II is regulated by the androgen receptor in prostate cancer Endocr. Relat. Cancer, September 1, 2007; 14(3): 613 - 624. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-T. Wu, W.-C. Chen, S.-K. Liao, C.-L. Hsu, K.-D. Lee, and M.-F. Chen The radiation response of hormone-resistant prostate cancer induced by long-term hormone therapy Endocr. Relat. Cancer, September 1, 2007; 14(3): 633 - 643. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Nakauchi, K.-i. Matsuda, I. Ochiai, A. Kawauchi, Y. Mizutani, T. Miki, and M. Kawata A Differential Ligand-mediated Response of Green Fluorescent Protein-tagged Androgen Receptor in Living Prostate Cancer and Non-prostate Cancer Cell Lines J. Histochem. Cytochem., June 1, 2007; 55(6): 535 - 544. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tamura, M. Furihata, T. Tsunoda, S. Ashida, R. Takata, W. Obara, H. Yoshioka, Y. Daigo, Y. Nasu, H. Kumon, et al. Molecular Features of Hormone-Refractory Prostate Cancer Cells by Genome-Wide Gene Expression Profiles Cancer Res., June 1, 2007; 67(11): 5117 - 5125. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. P. Mahajan, Y. Liu, S. Majumder, M. R. Warren, C. E. Parker, J. L. Mohler, H. S. Earp, and Y. E. Whang Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation PNAS, May 15, 2007; 104(20): 8438 - 8443. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-C. Yang, Y.-C. Wang, S. Wei, L.-F. Lin, C.-S. Chen, C.-C. Lee, C.-C. Lin, and C.-S. Chen Peroxisome Proliferator-Activated Receptor {gamma}-Independent Suppression of Androgen Receptor Expression by Troglitazone Mechanism and Pharmacologic Exploitation Cancer Res., April 1, 2007; 67(7): 3229 - 3238. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. V. Heemers, T. J. Sebo, J. D. Debes, K. M. Regan, K. A. Raclaw, L. M. Murphy, A. Hobisch, Z. Culig, and D. J. Tindall Androgen Deprivation Increases p300 Expression in Prostate Cancer Cells Cancer Res., April 1, 2007; 67(7): 3422 - 3430. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Fan, T. Yanase, H. Morinaga, T. Okabe, M. Nomura, H. Daitoku, A. Fukamizu, S. Kato, R. Takayanagi, and H. Nawata Insulin-like Growth Factor 1/Insulin Signaling Activates Androgen Signaling through Direct Interactions of Foxo1 with Androgen Receptor J. Biol. Chem., March 9, 2007; 282(10): 7329 - 7338. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Dehm and D. J. Tindall Ligand-independent Androgen Receptor Activity Is Activation Function-2-independent and Resistant to Antiandrogens in Androgen Refractory Prostate Cancer Cells J. Biol. Chem., September 22, 2006; 281(38): 27882 - 27893. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Xia, J. Sung, W. Chowdhury, C.-l. Chen, N. Hoti, S. Shabbeer, M. Carducci, and R. Rodriguez Chronic Administration of Valproic Acid Inhibits Prostate Cancer Cell Growth In vitro and In vivo. Cancer Res., July 15, 2006; 66(14): 7237 - 7244. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. S. Lyons and K. L. Burnstein Vav3, a Rho GTPase Guanine Nucleotide Exchange Factor, Increases during Progression to Androgen Independence in Prostate Cancer Cells and Potentiates Androgen Receptor Transcriptional Activity Mol. Endocrinol., May 1, 2006; 20(5): 1061 - 1072. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Nettikadan, K. Radke, J. Johnson, J. Xu, M. Lynch, C. Mosher, and E. Henderson Detection and Quantification of Protein Biomarkers from Fewer than 10 Cells Mol. Cell. Proteomics, May 1, 2006; 5(5): 895 - 901. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Le, J. T. Arnold, K. K. McFann, and M. R. Blackman DHT and testosterone, but not DHEA or E2, differentially modulate IGF-I, IGFBP-2, and IGFBP-3 in human prostatic stromal cells Am J Physiol Endocrinol Metab, May 1, 2006; 290(5): E952 - E960. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Veeramani, T.-C. Yuan, S.-J. Chen, F.-F. Lin, J. E Petersen, S. Shaheduzzaman, S. Srivastava, R. G MacDonald, and M.-F. Lin Cellular prostatic acid phosphatase: a protein tyrosine phosphatase involved in androgen-independent proliferation of prostate cancer Endocr. Relat. Cancer, December 1, 2005; 12(4): 805 - 822. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. I. Scher and C. L. Sawyers Biology of Progressive, Castration-Resistant Prostate Cancer: Directed Therapies Targeting the Androgen-Receptor Signaling Axis J. Clin. Oncol., November 10, 2005; 23(32): 8253 - 8261. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kim, J. Lapointe, G. Kaygusuz, D. E. Ong, C. Li, M. van de Rijn, J. D. Brooks, and J. R. Pollack The Retinoic Acid Synthesis Gene ALDH1a2 Is a Candidate Tumor Suppressor in Prostate Cancer Cancer Res., September 15, 2005; 65(18): 8118 - 8124. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Chen, S. Meng, H. Wang, P. Bali, W. Bai, B. Li, P. Atadja, K. N. Bhalla, and J. Wu Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824 Mol. Cancer Ther., September 1, 2005; 4(9): 1311 - 1319. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Debes, B. Comuzzi, L. J. Schmidt, S. M. Dehm, Z. Culig, and D. J. Tindall p300 Regulates Androgen Receptor-Independent Expression of Prostate-Specific Antigen in Prostate Cancer Cells Treated Chronically with Interleukin-6 Cancer Res., July 1, 2005; 65(13): 5965 - 5973. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Titus, M. J. Schell, F. B. Lih, K. B. Tomer, and J. L. Mohler Testosterone and Dihydrotestosterone Tissue Levels in Recurrent Prostate Cancer Clin. Cancer Res., July 1, 2005; 11(13): 4653 - 4657. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Liu, S. Majumder, W. McCall, C. I. Sartor, J. L. Mohler, C. W. Gregory, H. S. Earp, and Y. E. Whang Inhibition of HER-2/neu Kinase Impairs Androgen Receptor Recruitment to the Androgen Responsive Enhancer Cancer Res., April 15, 2005; 65(8): 3404 - 3409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Liao, S. Tang, J. B. Thrasher, T. L. Griebling, and B. Li Small-interfering RNA-induced androgen receptor silencing leads to apoptotic cell death in prostate cancer Mol. Cancer Ther., April 1, 2005; 4(4): 505 - 515. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.-L. Cha, L. Qiu, C.-T. Chen, Y. Wen, and M.-C. Hung Emodin Down-Regulates Androgen Receptor and Inhibits Prostate Cancer Cell Growth Cancer Res., March 15, 2005; 65(6): 2287 - 2295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K Oosterhoff, J A. Grootegoed, and L. J Blok Expression profiling of androgen-dependent and -independent LNCaP cells: EGF versus androgen signalling Endocr. Relat. Cancer, March 1, 2005; 12(1): 135 - 148. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. W. Gregory, Y. E. Whang, W. McCall, X. Fei, Y. Liu, L. A. Ponguta, F. S. French, E. M. Wilson, and H. S. Earp III Heregulin-Induced Activation of HER2 and HER3 Increases Androgen Receptor Transactivation and CWR-R1 Human Recurrent Prostate Cancer Cell Growth Clin. Cancer Res., March 1, 2005; 11(5): 1704 - 1712. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Bai, B. He, and E. M. Wilson Melanoma Antigen Gene Protein MAGE-11 Regulates Androgen Receptor Function by Modulating the Interdomain Interaction Mol. Cell. Biol., February 15, 2005; 25(4): 1238 - 1257. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Salah, M. Maoz, I. Cohen, G. Pizov, D. Pode, M. S. Runge, and R. Bar-Shavit Identification of a novel functional androgen response element within hPar1 promoter: implications to prostate cancer progression FASEB J, January 1, 2005; 19(1): 62 - 72. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. J. Schmidt, H. Murillo, and D. J. Tindall Gene Expression in Prostate Cancer Cells Treated With the Dual 5 Alpha-Reductase Inhibitor Dutasteride J Androl, November 1, 2004; 25(6): 944 - 953. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Debes and D. J. Tindall Mechanisms of Androgen-Refractory Prostate Cancer N. Engl. J. Med., October 7, 2004; 351(15): 1488 - 1490. [Full Text] [PDF]
|
|
|
|
|
|
H. I Scher, G. Buchanan, W. Gerald, L. M Butler, and W. D Tilley Targeting the androgen receptor: improving outcomes for castration-resistant prostate cancer Endocr. Relat. Cancer, September 1, 2004; 11(3): 459 - 476. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Buchanan, M. Yang, A. Cheong, J. M. Harris, R. A. Irvine, P. F. Lambert, N. L. Moore, M. Raynor, P. J. Neufing, G. A. Coetzee, et al. Structural and functional consequences of glutamine tract variation in the androgen receptor Hum. Mol. Genet., August 15, 2004; 13(16): 1677 - 1692. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. N. Papandreou and C. J. Logothetis Bortezomib as a Potential Treatment for Prostate Cancer Cancer Res., August 1, 2004; 64(15): 5036 - 5043. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Wang, J. R. Theriault, H. He, J. Gong, and S. K. Calderwood Expression of a Dominant Negative Heat Shock Factor-1 Construct Inhibits Aneuploidy in Prostate Carcinoma Cells* J. Biol. Chem., July 30, 2004; 279(31): 32651 - 32659. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Cheng, D. Wang, Z. Wang, and E. T. H. Yeh SENP1 Enhances Androgen Receptor-Dependent Transcription through Desumoylation of Histone Deacetylase 1 Mol. Cell. Biol., July 1, 2004; 24(13): 6021 - 6028. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Liao, J. B. Thrasher, J. Holzbeierlein, S. Stanley, and B. Li Glycogen Synthase Kinase-3{beta} Activity Is Required for Androgen-Stimulated Gene Expression in Prostate Cancer Endocrinology, June 1, 2004; 145(6): 2941 - 2949. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Sivashanmugam, L. Tang, and Y. Daaka Interleukin 6 Mediates the Lysophosphatidic Acid-regulated Cross-talk between Stromal and Epithelial Prostate Cancer Cells J. Biol. Chem., May 14, 2004; 279(20): 21154 - 21159. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Shukla and S. Gupta Suppression of Constitutive and Tumor Necrosis Factor {alpha}-Induced Nuclear Factor (NF)-{kappa}B Activation and Induction of Apoptosis by Apigenin in Human Prostate Carcinoma PC-3 Cells: Correlation with Down-Regulation of NF-{kappa}B-Responsive Genes Clin. Cancer Res., May 1, 2004; 10(9): 3169 - 3178. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Heinlein and C. Chang Androgen Receptor in Prostate Cancer Endocr. Rev., April 1, 2004; 25(2): 276 - 308. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Paronetto, D. Farini, I. Sammarco, G. Maturo, G. Vespasiani, R. Geremia, P. Rossi, and C. Sette Expression of a Truncated Form of the c-Kit Tyrosine Kinase Receptor and Activation of Src Kinase in Human Prostatic Cancer Am. J. Pathol., April 1, 2004; 164(4): 1243 - 1251. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rahman, H. Miyamoto, and C. Chang Androgen Receptor Coregulators in Prostate Cancer: Mechanisms and Clinical Implications Clin. Cancer Res., April 1, 2004; 10(7): 2208 - 2219. [Full Text] [PDF]
|
|
|
|
|
|
C. W. Gregory, X. Fei, L. A. Ponguta, B. He, H. M. Bill, F. S. French, and E. M. Wilson Epidermal Growth Factor Increases Coactivation of the Androgen Receptor in Recurrent Prostate Cancer J. Biol. Chem., February 20, 2004; 279(8): 7119 - 7130. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Daaka G Proteins in Cancer: The Prostate Cancer Paradigm Sci. Signal., January 20, 2004; 2004(216): re2 - re2. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Mohler, C. W. Gregory, O. H. Ford III, D. Kim, C. M. Weaver, P. Petrusz, E. M. Wilson, and F. S. French The Androgen Axis in Recurrent Prostate Cancer Clin. Cancer Res., January 15, 2004; 10(2): 440 - 448. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Debes, T. J. Sebo, C. M. Lohse, L. M. Murphy, D. A. L. Haugen, and D. J. Tindall p300 in Prostate Cancer Proliferation and Progression Cancer Res., November 15, 2003; 63(22): 7638 - 7640. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Uemura, H. Ishiguro, N. Nakaigawa, Y. Nagashima, Y. Miyoshi, K. Fujinami, A. Sakaguchi, and Y. Kubota Angiotensin II receptor blocker shows antiproliferative activity in prostate cancer cells: A possibility of tyrosine kinase inhibitor of growth factor Mol. Cancer Ther., November 1, 2003; 2(11): 1139 - 1147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Bookout, A. E. Finney, R. Guo, K. Peppel, W. J. Koch, and Y. Daaka Targeting G{beta}{gamma} Signaling to Inhibit Prostate Tumor Formation and Growth J. Biol. Chem., September 26, 2003; 278(39): 37569 - 37573. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hara, K. Nakamura, H. Araki, M. Kusaka, and M. Yamaoka Enhanced Androgen Receptor Signaling Correlates with the Androgen-refractory Growth in a Newly Established MDA PCa 2b-hr Human Prostate Cancer Cell Subline Cancer Res., September 1, 2003; 63(17): 5622 - 5628. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. W. Marshall, K. A. Link, C. E. Petre-Draviam, and K. E. Knudsen Differential Requirement of SWI/SNF for Androgen Receptor Activity J. Biol. Chem., August 15, 2003; 278(33): 30605 - 30613. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Zhang, M. Johnson, K. H. Le, M. Sato, R. Ilagan, M. Iyer, S. S. Gambhir, L. Wu, and M. Carey Interrogating Androgen Receptor Function in Recurrent Prostate Cancer Cancer Res., August 1, 2003; 63(15): 4552 - 4560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. PAKNESHAN, R. H. XING, and S. A. RABBANI Methylation status of uPA promoter as a molecular mechanism regulating prostate cancer invasion and growth in vitro and in vivo FASEB J, June 1, 2003; 17(9): 1081 - 1088. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Rahman, H. Miyamoto, H. Takatera, S. Yeh, S. Altuwaijri, and C. Chang Reducing the Agonist Activity of Antiandrogens by a Dominant-negative Androgen Receptor Coregulator ARA70 in Prostate Cancer Cells J. Biol. Chem., May 23, 2003; 278(22): 19619 - 19626. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Baldi, L. Bonaccorsi, and G. Forti Androgen Receptor: Good Guy or Bad Guy in Prostate Cancer Invasion? Endocrinology, May 1, 2003; 144(5): 1653 - 1655. [Full Text] [PDF]
|
|
|
|
|
|
R. E. Bakin, D. Gioeli, R. A. Sikes, E. A. Bissonette, and M. J. Weber Constitutive Activation of the Ras/Mitogen-activated Protein Kinase Signaling Pathway Promotes Androgen Hypersensitivity in LNCaP Prostate Cancer Cells Cancer Res., April 15, 2003; 63(8): 1981 - 1989. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Farini, A. Puglianiello, C. Mammi, G. Siracusa, and C. Moretti Dual Effect of Pituitary Adenylate Cyclase Activating Polypeptide on Prostate Tumor LNCaP Cells: Short- and Long-Term Exposure Affect Proliferation and Neuroendocrine Differentiation Endocrinology, April 1, 2003; 144(4): 1631 - 1643. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Santamaria, P. L. Fernandez, X. Farre, P. Benedit, J. Reventos, J. Morote, R. Paciucci, and T. M. Thomson PTOV-1, a Novel Protein Overexpressed in Prostate Cancer, Shuttles between the Cytoplasm and the Nucleus and Promotes Entry into the S Phase of the Cell Division Cycle Am. J. Pathol., March 1, 2003; 162(3): 897 - 905. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Adam, J. Kim, J. Lin, A. Orsola, L. Zhuang, D. C. Rice, and M. R. Freeman* Heparin-Binding Epidermal Growth Factor-Like Growth Factor Stimulates Androgen-Independent Prostate Tumor Growth and Antagonizes Androgen Receptor Function Endocrinology, December 1, 2002; 143(12): 4599 - 4608. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Debes, L. J. Schmidt, H. Huang, and D. J. Tindall p300 Mediates Androgen-independent Transactivation of the Androgen Receptor by Interleukin 6 Cancer Res., October 15, 2002; 62(20): 5632 - 5636. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. K. Mellinghoff, C. Tran, and C. L. Sawyers Growth Inhibitory Effects of the Dual ErbB1/ErbB2 Tyrosine Kinase Inhibitor PKI-166 on Human Prostate Cancer Xenografts Cancer Res., September 15, 2002; 62(18): 5254 - 5259. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Xia, D. Robinson, A.-H. Ma, H.-C. Chen, F. Wu, Y. Qiu, and H.-J. Kung Identification of Human Male Germ Cell-associated Kinase, a Kinase Transcriptionally Activated by Androgen in Prostate Cancer Cells J. Biol. Chem., September 13, 2002; 277(38): 35422 - 35433. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Simard, M. Dumont, P. Soucy, and F. Labrie Perspective: Prostate Cancer Susceptibility Genes Endocrinology, June 1, 2002; 143(6): 2029 - 2040. [Full Text] [PDF]
|
|
|
|
|
|
Y. B. Wetherill, C. E. Petre, K. R. Monk, A. Puga, and K. E. Knudsen The Xenoestrogen Bisphenol A Induces Inappropriate Androgen Receptor Activation and Mitogenesis in Prostatic Adenocarcinoma Cells Mol. Cancer Ther., May 1, 2002; 1(7): 515 - 524. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||