Androgen receptor corepressors and prostate cancer

The androgen receptor (AR) mediates the effects of male steroid hormones (androgens) and contributes to a wide variety of physiological and pathophysiological conditions. As such, the regulatory mechanisms governing AR activity are of high significance. Concerted effort has been placed on delineating the mechanisms that control AR activity in prostate cancer, as AR is required for survival and proliferation in this tumor type. Moreover, AR is the central therapeutic target for metastatic prostate cancers, and recurrent tumors evade therapy by restoring AR activity. It is increasingly apparent that AR cofactors which modulate receptor activity can contribute to prostate cancer growth or progression, and this has been particularly well established for AR coactivators. The present review is focused on the role of AR corepressors in governing androgen action, with a specific emphasis on their activities in prostate cancer.     

Androgen receptor gene mutations in human prostate cancer.

We screened human prostate cancer tissues for the presence of somatic mutations in the hormone binding domain of the androgen receptor (AR) gene. Exons E-H were amplified from genomic DNA using the polymerase chain reaction and analyzed by denaturing gradient gel electrophoresis (DGGE), which separates DNA fragments that differ by only a single base. We detected a mutation in exon E of the hormone binding domain in 1 of 26 specimens of untreated organ-confined stage B prostate cancer. The mutation was not detectable in peripheral blood lymphocyte DNA. Lymphocyte DNA (wild-type AR) migrated in DGGE as a single band. The tumor DNA migrated in DGGE as four bands, consistent with the presence of cells with mutant AR plus cells with wild-type AR and indicating that the tumor contained a somatic mutation. To our knowledge, a somatic AR gene mutation has not been reported previously. Sequencing revealed a G----A substitution in codon 730, changing valine to methionine. Codon 730 is in a region highly conserved among all steroid receptors. The abundance of the mutated fragment (about 50% of the DNA in the specimen) indicates its presence in cells with a growth advantage. A somatic mutation could be detected by DGGE if it represented at least 10% of the sample. Failure to detect mutations in other specimens analyzed may be due to this limit of sensitivity, the presence of mutations in other parts of the AR, or a low frequency of mutations in early stage disease.     

Androgen metabolism in the epithelial and stromal components of the human hyperplastic prostate

The reduced and oxidized metabolites of testosterone and dihydrotestosterone were measured in the stromal and epithelial components of 23 human hyperplastic prostates. Our studies indicate differences in the hormonal metabolic patterns of the stroma and epithelium of the resected specimens when compared with tissues obtained retropubically. Testosterone 5 alpha-reductase was evenly distributed between the two components of the specimens obtained retropubically whereas the 3 alpha (beta)-hydroxysteroid dehydrogenase was predominantly located in the stroma. The measurements on the resected specimens suggest, on the other hand, that the bulk of the 5 alpha reductase and 3 alpha (beta)-hydroxysteroid dehydrogenase activities were confined to the stroma although these activities were considerably lower than those measured in the corresponding components of the retropublically obtained specimens. The conversion of testosterone to androstenedione was negligible in all the samples analysed. We therefore conclude that the stroma is the main site for the transformation of dihydrotestosterone to the androstanediol epimers and that the asymmetric distribution of the 3 alpha (beta)-hydroxysteroid dehydrogenase may be instrumental in the development of hyperplasia in the prostate gland. Furthermore, the results of this study indicate that electroresection impairs the enzymatic activities of the tissue.     

Androgen receptor is a tumor suppressor and proliferator in prostate cancer

Targeting androgens/androgen receptor (AR) functions via androgen deprivation therapy (ADT) remains the standard treatment for prostate cancer. However, most tumors eventually recur despite ADT. Here we demonstrate that the prostate AR may function as both a suppressor and a proliferator to suppress or promote prostate cancer metastasis. Results from orthotopically recombining stromal WPMY1 cells with epithelial PC3 prostate cancer cells in mice demonstrated that restoring AR in epithelial PC3 cells or knockdown of AR in stromal WPMY1 cells suppressed prostate cancer metastasis. Knockdown of the AR in epithelial CWR22rv1 prostate cancer cells also resulted in increased cell invasion in vitro and in vivo. Restoring AR in PC3 cells (PC3-AR9) results in decreased invasion in bone lesion assays and in vivo mouse models. Mice lacking the prostate epithelial AR have increased apoptosis in epithelial luminal cells and increased proliferation in epithelial basal cells. The consequences of these two contrasting results led to the expansion of CK5/CK8-positive intermediate cells, and mice developed larger and more invasive metastatic tumors in lymph nodes and died earlier than wild-type littermates. Mechanistic dissection suggested that androgens/AR might directly or indirectly modulate metastasis-related genes and suppression of TGFβ1 signals results in the partial inhibition of AR-mediated metastasis. Collectively, our understanding of these opposing roles of prostatic AR may revolutionize the way we combat prostate cancer, and allow the development of new and better therapies by targeting only the proliferative role of AR.     

前列腺癌雄激素剥夺治疗与动脉粥样硬化的代谢风险

前列腺癌(PCa)是男性最常见的一种肿瘤,其发病率因前列腺特异性抗原(PSA)检测的开展而增高.2007年美国新增PCa约219 000例,死亡约27 000例(仅次于肺癌).1941年Huggins等报道去势可以减缓PCa的生长,提示其有雄激素依赖性.     

Androgen deprivation therapy in prostate cancer and metabolic risk for atherosclerosis

CONTEXT: Prostate cancer (PCa) is the most common cancer in men. Androgen-deprivation therapy (ADT) is generally employed in the treatment of locally advanced and metastatic PCa. Although its use as an adjuvant therapy has resulted in improved survival in some patients, ADT has negative consequences. Complications like osteoporosis, sexual dysfunction, gynecomastia, and adverse body composition are well known. Recently, metabolic complications like insulin resistance, diabetes, dyslipidemia, and metabolic syndrome have emerged, which may be responsible for the increased cardiovascular mortality in this population. EVIDENCE ACQUISITION: A MEDLINE search was conducted for articles published over the last 20 yr based on the key words androgen deprivation therapy AND insulin resistance, hyperglycemia, diabetes, dyslipidemia, metabolic syndrome, and cardiovascular disease. Relevant studies in non-PCa populations evaluating the association between testosterone and metabolism were also reviewed and briefly mentioned where relevant. EVIDENCE SYNTHESIS: Prospective studies evaluating early (3-6 months) metabolic changes of ADT show development of hyperinsulinemia; however, glucose levels remain normal. Cross-sectional studies of men undergoing long-term (> or =12 months) ADT reveal higher prevalence of diabetes and metabolic syndrome compared with controls. Furthermore, men undergoing ADT also experience higher cardiovascular mortality. CONCLUSION: Long-term prospective studies of ADT are needed to determine the timing of onset of these metabolic complications and to investigate the mechanism behind them. In the meantime, we recommend baseline and serial screening for fasting glucose, lipids, and other cardiovascular risk factors in men receiving ADT. Glucose tolerance tests and cardiac evaluation may be required in selected cases.     

Androgen receptor and growth factor signaling cross-talk in prostate cancer cells

Androgens promote the growth and differentiation of prostate cells through ligand activation of the androgen receptor (AR). Sensitization of the androgenic response by multifunctional growth factor signaling pathways is one of the mechanisms via which AR contributes to the emergence of androgen-independent prostate tumors. The ability of AR to cross-talk with key growth factor signaling events toward the regulation of cell cycle, apoptosis, and differentiation outcomes in prostate cancer cells is established. In this paper, we review the functional interaction between AR and an array of growth factor signal transduction events (including epidermal growth factor; fibroblast growth factor; IGF1; vascular endothelial growth factor; transforming growth factor-beta) in prostate tumors. The significance of this derailed cross-talk between androgens and key signaling networks in prostate cancer progression and its value as a therapeutic forum targeting androgen-independent metastatic prostate cancer is discussed.     

Androgen receptor in prostate cancer: cause or cure?

Growth of prostate tumours is dependent on androgens. Hence, therapy involves removing androgens and opposing their effects using antiandrogens. This is initially successful but inevitably fails and tumours recur. The cause of this transition to hormone-independence, and the precise role of the androgen receptor in this, is a matter of considerable debate. A recent study used a mouse model to assess the effects of increased androgen receptor expression in the prostate and found that, whereas increased expression of wild-type receptor had no effect, a mutation of the androgen receptor caused it to have oncogenic properties. This goes some way to elucidating how the androgen receptor affects tumour growth, and provides an exciting model for further study of androgen receptor mutations in prostate cancer.     

Androgen receptor (AR) aberrations in castration-resistant prostate cancer

Genetic aberrations affecting the androgen receptor (AR) are rare in untreated prostate cancers (PCs) but have been found in castration-resistant prostate cancers (CRPCs). Further, successful treatment with novel endocrine therapies indicates that CRPCs remain androgen-sensitive. Known AR aberrations include amplification of the AR gene leading to the overexpression of the receptor, point mutations of AR resulting in promiscuous ligand usage, and constitutively active AR splice variants. Gain, or amplification, of the AR gene is one of the most frequent genetic alterations observed in CRPCs. Up to 80% of CRPCs have been reported to carry an elevated AR gene copy number, and about 30% have a high-level amplification of the gene. AR mutations are also commonly observed and have been found in approximately 10-30% of the CRPC treated with antiandrogens; however, the frequency and significance of AR splice variants is still unclear. Because AR aberrations are found almost exclusively in CRPC, these alterations must have been selected for during therapy. Interestingly, these aberrations lead to activation of the receptor, despite treatment-induced emergence of therapy-resistant tumor clones. Therefore, future novel treatment strategies should focus on suppressing AR activity in CRPC.     

Androgen receptor levels are upregulated by Akt in prostate cancer

Multiple lines of evidence suggest a functional link between the androgen receptor (AR) and the serine/threonine kinase Akt in the development and progression of prostate cancer. To investigate the impact of Akt activity on AR homeostasis, we treated androgen-dependent LNCaP and LAPC-4 prostate cancer cells with Akt inhibitor. Akt inhibition decreased AR expression, suggesting that Akt activity was required for regulation of AR protein levels. However, while androgen-independent LNCaP-abl cells also showed diminished AR protein levels in response to Akt inhibition, treatment of androgen-independent LNCaP-AI cells failed to alter AR protein levels upon similar treatment, suggesting that AR protein levels in these androgen-independent prostate cells were regulated by mechanisms independent of Akt activation. Regulation of AR, downstream of activated Akt, also was observed in vivo when examining transgenic mice that overexpress constitutively active mutant myristoylated (myr)-Akt1 in the prostate. Transgenic mice expressing activated myr-Akt1 exhibited higher levels of AR mRNA and protein. Expression of activated myr-Akt1 did not alter prostate cell growth and no significant size differences between prostate tissues derived from transgenic animals were observed when comparing transgenic mice with wild-type mice. Still, transgenic mice overexpressing Akt exhibited higher levels of γH2AX and phosphorylated Chk2 in prostate tissue. These changes in markers associated with oncogene-induced senescence confirmed significant altered signaling in the transgenic mouse model. Overall, results presented here suggest that AR levels are regulated by the Akt pathway.     

Androgen receptor decoy molecules block the growth of prostate cancer

The androgen receptor (AR) is activated by both ligand-dependent and -independent mechanisms. Current therapies for prostate cancer target the ligand-binding domain in the C terminus of the AR. However, ligand-independent activation of the AR occurs by the N-terminal domain (NTD), making the NTD a potential novel target for the treatment of hormone refractory prostate cancer. A possible therapeutic approach is to overexpress an AR NTD peptide to create decoy molecules that competitively bind the interacting proteins required for activation of the endogenous full-length AR. We provide evidence that in vivo expression of AR NTD decoys decreased tumor incidence and inhibited the growth of prostate cancer tumors. This growth inhibition was characterized by a 10-fold decrease in serum levels of prostate-specific antigen (PSA) (46.7 ng/ml+/-19.9 vs. 432.4 ng/ml+/-201.3; P=0.0299) and a 4-fold decrease in tumor volume (92.2 mm3+/-43.4 vs. 331.4 mm3+/-85.5; P=0.011). AR NTD decoy molecules also delayed hormonal progression, as determined by time to rising PSA levels after castration of the host. The tumors treated with AR NTD decoys contained more apoptotic cells and fewer proliferating cells, whereas no effect was seen on the viability of cells that did not depend on the AR. This work provides further evidence of the importance of the NTD of the AR in the progression of prostate cancer and presents a target for the development of antagonists of the AR in the clinical management of this disease.