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Background: Although Black men are more likely than non‐Hispanic White men to develop and die from prostate cancer, limited data exist to guide prostate‐specific antigen (PSA) screening protocols in Black men. This study investigated whether the risk for prostate cancer was higher than expected among self‐identified Black than White veterans based on prebiopsy PSA level. Methods: Multivariable logistic regression models were estimated to predict the likelihood of prostate cancer diagnosis on first biopsy for 75,295 Black and 207,658 White male veterans. Self‐identified race, age at first PSA test, prebiopsy PSA, age at first biopsy, smoking status, statin use, and socioeconomic factors were used as predictors. The adjusted predicted probabilities of cancer detection on first prostate biopsy from the logistic models at different PSA levels were calculated. Results: After controlling for PSA and other covariates, Black veterans were 50% more likely to receive a prostate cancer diagnosis on their first prostate biopsy than White veterans (odds ratio [OR], 1.50; 95% CI, 1.47‐1.53; p <.001). At a PSA level of 4.0 ng/mL, the probability of prostate cancer for a Black man was 49% compared with 39% for a White man. This model indicated that Black veterans with a PSA of 4.0 ng/mL have an equivalent risk of prostate cancer as White veterans with a PSA of 13.4 ng/mL. Conclusions: The findings indicate that, at any given PSA level, Black men are more likely to harbor prostate cancer than White men. Prospective studies are needed to better evaluate risks and benefits of PSA screening in Black men and other high‐risk populations. At any given prostate‐specific antigen level, Black men have substantially higher risk of prostate cancer detection on their first biopsy compared with White men after accounting for socioeconomic factors, age, and prebiopsy prostate‐specific antigen. This difference was more pronounced among younger men. [ABSTRACT FROM AUTHOR]

This article explores the role of regulatory T cells (Tregs) in prostate cancer (PCa) and their impact on prognosis and treatment response. The researchers found that Tregs can be divided into two subtypes: TregR, which is associated with a poor prognosis, immunosuppression, and resistance to therapy, and TregP, which has the opposite characteristics. TregR showed higher expression of TGF-β and mutations in the TP53 and PIK3CA genes, which may contribute to therapy resistance. The study suggests that targeting TGF-β and the PI3K-AKT-mTOR pathway may improve treatment outcomes for TregR PCa. [Extracted from the article]

Clinical and genomic features of prostate cancer (PCa) vary considerably between Asian and Western populations. PTEN loss is the most frequent abnormality in intraductal carcinoma of the prostate (IDC‐P) in Western populations. However, its prevalence and significance in Asian populations have not yet been well studied. In the present study, we evaluated PTEN expression in IDC‐P in a Japanese population and its association with ERG expression. This study included 45 and 59 patients with PCa with and without IDC‐P, respectively, who underwent radical prostatectomy. PTEN loss was observed in 10 patients with PCa with IDC‐P (22%) and nine patients with PCa without IDC‐P (17%). ERG expression was relatively frequent in patients with PCa with PTEN loss, although a significant difference was not observed. The co‐occurrence of PTEN loss and ERG expression was observed in four patients with PCa with IDC‐P and one without IDC‐P. PTEN loss and ERG expression did not affect progression‐free survival, regardless of the presence of IDC‐P. The frequency of PTEN loss in IDC‐P is lower in Asian patients than in Western patients. Our results indicate that mechanisms underlying IDC‐P in Asian populations are different from those of Western populations. [ABSTRACT FROM AUTHOR]

Androgen receptor (AR) signaling have been frequently targeted for treating prostate cancer (PCa). Even though primarily patients receive a good therapeutic outcome by targeting AR signaling axis, eventually it emerges resistance by altering the genetic makeup of prostate cells. However, to develop an effective therapeutic regime, it is essential to recognize key genetic alterations in PCa. The most common genetic alterations that give rise to distinct androgen different differentiation states are gene fusion of TMPRSS2 with ETS family genes, deletion, or mutation of tumor suppressor PTEN and TP53 gene, amplification or splicing of AR, altered DNA repair genes. In this review, we describe key genes and genetic changes that have been recognized to contribute to altered prostate environment. [ABSTRACT FROM AUTHOR]

A review of the current treatment options for prostate cancer and the formation of resistance to these regimens has been compiled including primary, acquired, and cross‐resistance. The diversification of the pathways involved and the escape routes the tumor is utilizing have been addressed. Whereas early stages of tumor can be cured, there is no treatment available after a point of no return has been reached, leaving palliative treatment as the only option. The major reasons for this outcome are the heterogeneity of tumors, both inter‐ and intra‐individually and the nearly endless number of escape routes, which the tumor can select to overcome the effects of treatment. This means that more focus should be applied to the individualization of both diagnosis and therapy of prostate cancer. In addition to current treatment options, novel drugs and ongoing clinical trials have been addressed in this review. [ABSTRACT FROM AUTHOR]

Cholinergic receptor muscarinic 3 (CHRM3)‐mediated focal adhesion kinase/YES‐associated protein (YAP) signalling is essential for the growth of castration‐resistant prostate cancer (CRPC) cells. Here, we evaluated the molecular mechanisms through which CHRM3 overexpression facilitates castration‐resistant growth. Small RNA sequencing combined with in silico analyses revealed that CHRM3 was a putative target of miR‐15b‐5p. Notably, androgen deprivation suppressed miR‐15b‐5p expression and increased CHRM3 expression. Moreover, miR‐15b‐5p bound directly to CHRM3 and inhibited YAP activation induced by CHRM3 stimulation. Furthermore, miR‐15b‐5p abolished the growth of CRPC cells induced by CHRM3 stimulation. We conclude that the miR‐15b‐5p/CHRM3/YAP signalling axis promotes the castration‐resistant growth of prostate cancer. [ABSTRACT FROM AUTHOR]

Hippo signaling restricts tumor growth by inhibiting the oncogenic potential of YAP/TAZ‐TEAD transcriptional complex. Here, we uncover a context‐dependent tumor suppressor function of YAP in androgen receptor (AR) positive prostate cancer (PCa) and show that YAP impedes AR+ PCa growth by antagonizing TEAD‐mediated AR signaling. TEAD forms a complex with AR to enhance its promoter/enhancer occupancy and transcriptional activity. YAP and AR compete for TEAD binding and consequently, elevated YAP in the nucleus disrupts AR‐TEAD interaction and prevents TEAD from promoting AR signaling. Pharmacological inhibition of MST1/2 or LATS1/2, or transgenic activation of YAP suppressed the growth of PCa expressing therapy resistant AR splicing variants. Our study uncovers an unanticipated crosstalk between Hippo and AR signaling pathways, reveals an antagonistic relationship between YAP and TEAD in AR+ PCa, and suggests that targeting the Hippo signaling pathway may provide a therapeutical opportunity to treat PCa driven by therapy resistant AR variants. Synopsis: Deviating from its established oncogenic function, this study uncovers a context‐dependent tumor suppressor role of Hippo signalling pathway effector YAP in androgen receptor (AR)‐positive prostate cancer (PCa), and unexpected crosstalk between Hippo and AR signalling. TEAD forms a transcriptional complex with AR in PCa increasing its promoter and enhancer occupancy.Elevated nuclear YAP inhibits AR activity by competing for TEAD binding.Small molecule Hippo pathway inhibition or transgenic YAP activation decrease AR+ PCa growth. [ABSTRACT FROM AUTHOR]

Androgen receptor (AR) is a master transcription factor that drives prostate cancer (PCa) development and progression. Alterations in the expression or activity of AR coregulators significantly impact the outcome of the disease. Using a proteomics approach, we identified the tripartite motif‐containing 33 (TRIM33) as a novel transcriptional coactivator of AR. We demonstrate that TRIM33 facilitates AR chromatin binding to directly regulate a transcription program that promotes PCa progression. TRIM33 further stabilizes AR by protecting it from Skp2‐mediated ubiquitination and proteasomal degradation. We also show that TRIM33 is essential for PCa tumor growth by avoiding cell‐cycle arrest and apoptosis, and TRIM33 knockdown sensitizes PCa cells to AR antagonists. In clinical analyses, we find TRIM33 upregulated in multiple PCa patient cohorts. Finally, we uncover an AR‐TRIM33‐coactivated gene signature highly expressed in PCa tumors and predict disease recurrence. Overall, our results reveal that TRIM33 is an oncogenic AR coactivator in PCa and a potential therapeutic target for PCa treatment. Synopsis: TRIM33 is an oncogenic coactivator of AR‐dependent transcription in prostate cancer. TRIM33 exerts its coactivator activity by stabilizing AR from Skp2‐mediated ubiquitination and proteasomal degradation. TRIM33 coactivates AR‐mediated transcription in prostate cancer (PCa) by stabilizing AR from Skp2‐mediated ubiquitination and proteasomal degradation.TRIM33 is highly expressed in PCa tumors and is required for prostate tumor growth.TRIM33 and AR target genes define an AR‐TRIM33‐coactivated gene signature that is highly expressed in PCa tumors. Patients with a high expression of this gene signature show a higher risk of disease recurrence. [ABSTRACT FROM AUTHOR]

This study aimed to elucidate the role of ELF3, an ETS family member in normal prostate growth and prostate cancer. Silencing ELF3 in both benign prostate (BPH-1) and prostate cancer (PC3) cell lines resulted in decreased colony-forming ability, inhibition of cell migration and reduced cell viability due to cell cycle arrest, establishing ELF3 as a cell cycle regulator. Increased ELF3 expression in more advanced prostate tumours was shown by immunostaining of tissue microarrays and from analysis of gene expression and genetic alteration studies. This study indicates that ELF3 functions not only as a part of normal prostate epithelial growth but also as a potential oncogene in advanced prostate cancers. [ABSTRACT FROM AUTHOR]

Prostate cancer is one of the predominant cancers affecting men and has been widely reported. In the past, various therapies and drugs have been proposed to treat prostate cancer. Among these treatments, gene therapy has been considered to be an optimal and widely applicable treatment. Furthermore, due to the increased specificity of gene sequence complementation, the targeted delivery of complementary gene sequences may represent a useful treatment in certain instances. Various gene therapies, including tumor‐suppressor gene therapy, suicide gene therapy, immunomodulation gene therapy and anti‐oncogene therapies, have been established to treat a wide range of diseases, such as cardiac disease, cystic fibrosis, HIV/AIDS, diabetes, hemophilia, and cancers. To this end, several gene therapy clinical trials at various phases are underway. This overview describes the developments and progress in gene therapy, with a special focus being placed on prostate cancer. [ABSTRACT FROM AUTHOR]

Objective: To compare oncological outcomes in men with clinical T3b prostate cancer who underwent radical prostatectomy or a combination of radiation therapy plus androgen deprivation therapy. Methods: Men with clinical T3b prostate cancer who underwent radical prostatectomy or radiation therapy plus androgen deprivation therapy between 2007 and 2014 were evaluated. All patients were relatively healthy, with Eastern Cooperative Oncology Group performance status of 0 or 1 without nodal or distant metastasis. Cancer‐specific survival was analyzed. Age, Charlson Comorbidity Index, biopsy Gleason score and pretreatment prostate‐specific antigen were adjusted by propensity score matching. The Cox proportional hazards model was used to assess factors prognostic of cancer‐specific survival. Results: Of the 152 patients with clinical T3b prostate cancer, 45 underwent radical prostatectomy, and 107 underwent radiation therapy plus androgen deprivation therapy between 2007 and 2014. The mean cancer‐specific survival was significantly longer in the radical prostatectomy than in the radiation therapy plus androgen deprivation therapy group (P = 0.029). Age, Charlson Comorbidity Index and pretreatment prostate‐specific antigen were significantly higher in the radiation therapy plus androgen deprivation therapy group. In the propensity score matched population of 24 patients each, the median cancer‐specific survival remained significantly longer in the radical prostatectomy than in the radiation therapy plus androgen deprivation therapy group (not reached vs 112.93 ± 11.94 months, P = 0.026). Multivariate analysis showed that undergoing radiation therapy plus androgen deprivation therapy was the only significant poor prognostic factor for cancer‐specific survival (hazard ratio 6.694, 95% confidence interval 1.642–27.592, P = 0.008). Conclusion: Cancer‐specific survival was significantly longer in men with clinical T3b prostate cancer who underwent radical prostatectomy than radiation therapy plus androgen deprivation therapy, suggesting that radical prostatectomy can be a better treatment option for the initial definitive treatment for these patients. [ABSTRACT FROM AUTHOR]

Despite the clinical benefit of androgen‐deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration‐resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, we show that the ER membrane‐associated protein THEM6 regulates intracellular levels of ether lipids and is essential to trigger the induction of the ER stress response (UPR). Consequently, THEM6 loss in CRPC cells significantly alters ER function, reducing de novo sterol biosynthesis and preventing lipid‐mediated activation of ATF4. Finally, we demonstrate that high THEM6 expression is associated with poor survival and correlates with high levels of UPR activation in PCa patients. Altogether, our results highlight THEM6 as a novel driver of therapy resistance in PCa as well as a promising target for the treatment of CRPC. Synopsis: Resistance to androgen‐deprivation therapy (ADT) leads to the development of lethal castration‐resistant prostate cancer. This study highlights THEM6 as a clinically relevant protein that supports ADT‐induced rewiring of lipid metabolism and sustains UPR activation, thus promoting ADT resistance. THEM6 is overexpressed in ADT‐resistant tumours and supports PCa tumour growth in androgen‐deprived conditions.Loss of THEM6 significantly alters the cellular lipidome of CRPC cells, resulting in decreased levels of ether lipids.THEM6 is an ER‐membrane protein that physically interacts with several components of the protein trafficking machinery.Loss of THEM6 significantly affects ER function, reducing de novo sterol synthesis and impairing lipid‐mediated activation of the UPR, two processes that promote ADT resistance.High THEM6 expression in tumour biopsies is associated with shortened patient survival and correlates with sustained UPR activation, thus highlighting the potential of THEM6 as a therapeutic target in CRPC. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCa), an inert tumour, has a long progression period, but valid biomarkers and methods for effectively and sensitively monitoring PCa progression are lacking, prompting us to identify new predictors for diagnosis and prognosis. Posttranslational modifications characterizing receptor activation are considered potentially strong indicators of disease progression. Methods: The posttranscriptional regulation of leukaemia inhibitory factor receptor (LIFR) and its novel downstream signalling activity in PCa were studied using liquid mass spectrometry, genetically engineered mouse (GEM) models, organoid assays, lentivirus packaging, infection and stable cell line construction. Results: In this study, the level of acetylated K620 on LIFR in its extracellular domain was shown to predict the progression and prognosis of PCa. In PCa cells, LIFR‐K620 acetylation is reversibly mediated by GCN5 and SIRT2. GEM experiments and organoid assays confirmed that the loss of LIFR‐K620 acetylation inhibits PCa progression. Mechanistically, K620 acetylation facilitates LIFR homodimerization and subsequently promotes LIFR‐S1044 phosphorylation and activation, which further recruits PDPK1 to activate AKT signalling and sequentially enhances the GCN5 protein level to sustain the protumour level of LIFR‐K620 acetylation by preventing GCN5 degradation via CRL4Cdt2 E3 ligase. Conclusions: Acetylation of extracellular K620 on LIFR reinforces its homodimerization and integrates the activities of PDPK1, AKT, GSK3β and GCN5 to form a novel positive feedback loop in PCa; this modification is thus a promising biomarker for monitoring PCa progression. [ABSTRACT FROM AUTHOR]

Both androgen receptor (AR) and the ZFHX3 transcription factor modulate prostate development. While AR drives prostatic carcinogenesis, ZFHX3 is a tumour suppressor whose loss activates the PI3K/AKT signalling in advanced prostate cancer (PCa). However, it is unknown whether ZFHX3 and AR are functionally related in PCa cells and, if so, how. Here, we report that in AR‐positive LNCaP and C4‐2B PCa cells, androgen upregulates ZFHX3 transcription via androgen‐induced AR binding to the androgen‐responsive elements (AREs) of the ZFHX3 promoter. Androgen also upregulated ZFHX3 transcription in vivo, as castration dramatically reduced Zfhx3 mRNA and protein levels in mouse prostates, and ZFHX3 mRNA levels correlated with AR activities in human PCa. Interestingly, the binding of AR to one ARE occurred in the absence of androgen, and the binding repressed ZFHX3 transcription as this repressive binding was interrupted by androgen treatment. The enzalutamide antiandrogen prevented androgen from inducing ZFHX3 transcription and caused excess ZFHX3 protein degradation. In human PCa, ZFHX3 was downregulated and the downregulation correlated with worse patient survival. These findings establish a regulatory relationship between AR and ZFHX3, suggest a role of ZFHX3 in AR function and implicate ZFHX3 loss in the antiandrogen therapies of PCa. [ABSTRACT FROM AUTHOR]

Background: This study assessed the contrasting genomic profiles from the primary tumors (PTs), metastatic (MET) sites, and circulating tumor DNA (ctDNA) of patients with prostate cancer (PC). Methods: A total of 1294 PC tissue specimens and 2462 ctDNA specimens underwent hybrid capture–based comprehensive genomic profiling (CGP). Specimens included tissue from PTs; MET biopsies from bone, liver (LIV), lung (LU), brain (BN), lymph node, and soft tissue sites; and ctDNA. Results: Differences in alteration frequencies between PT, MET, and ctDNA specimens for selected genes were observed. TMPRSS2:ERG fusion frequencies were similar between PTs and MET sites (35% vs 33%) but varied among MET sites. Genomic alterations (GAs) in AR were lowest in PTs (2%) and highest in MET sites (from 24% in LU to 50% in LIV). BN had the highest genomic alterations/tumor (8) and enrichment for PTEN GAs. The BRCA2 GA frequency varied from 0% in BN to 15% in LIV. ERBB2 amplification was increased in MET sites in comparison with PTs. RB1 GAs were increased in LIV. Biomarkers potentially associated with an anti‐PD(L)1 response included CDK12 GAs (16% in LU) and a microsatellite instability–high status (29% in BN). Analyses of ctDNA featured a broad spectrum of GAs similar to those detected across MET sites. Conclusions: CGP of PTs, MET sites, and ctDNA in PC exhibited differences most likely associated with tumor progression, clonal evolution, and exposure to systemic therapies; ctDNA can also capture a broad range of potential therapeutic opportunities for patients with PC. Tumor tissue genomic alterations from primary prostate tumors and metastatic sites show significant heterogeneity, and this suggests possible tumor evolution, natural selection, and/or tumor adaptation. Circulating tumor DNA testing can be a noninvasive, potentially serial assay that may provide a real‐time representation of the evolutionary cancer state throughout therapy. [ABSTRACT FROM AUTHOR]

Transcription factor SOX9 was a biomarker for prostate cancer (Pca) with poor prognosis. Nevertheless, the regulatory mechanism underlying SOX9 upregulation still remains unclear. Several cytokines have been reported to be involved in the regulation of SOX9, suggesting that cancer‐associated fibroblasts (CAFs), one of the main sources of secreted factors in the tumor microenvironment (TME), may play a role in regulating SOX9 expression. Herein, an in vitro model of paracrine interaction between primary CAFs and Pca cells was applied to investigate the molecular mechanism of SOX9 upregulation during Pca progression. The regulatory axis was validated by in vivo experiments and The Cancer Genome Atlas data. Conditional medium of CAFs (CAF‐CM) upregulated the expression of SOX9, which was mutually proved to be essential for CAF‐induced tumor progression. Further analysis showed that hepatocyte growth factor (HGF) secreted by CAFs was responsible for SOX9 elevation in Pca cells, via the activation of c‐Met signaling. Mechanistically, HGF/c‐Met signaling specifically activated MEK1/2‐ERK1/2 pathway, which induced phosphorylation and upregulation of FRA1, which then transcriptionally upregulated SOX9 by binding to the promoter of SOX9 gene. Moreover, we identified that HGF/c‐Met‐ERK1/2‐FRA1‐SOX9 axis was relatively conserved between human and mouse species by validating in mouse Pca cells. Our results reveal a novel insight into the molecular mechanism that SOX9 in Pca cells is promoted by CAFs through HGF/c‐Met‐ERK1/2‐FRA1 axis. Furthermore, SOX9 may serve as an alternative marker for the activated HGF/c‐Met signaling to enroll the optimal Pca patients for HGF/c‐Met inhibition treatment, since it is much more stable and easier to detect. [ABSTRACT FROM AUTHOR]

Treatment‐induced adaptive pathways converge to support androgen receptor (AR) reactivation and emergence of castration‐resistant prostate cancer (PCa) after AR pathway inhibition (ARPI). We set out to explore poorly defined acute adaptive responses that orchestrate shifts in energy metabolism after ARPI and identified rapid changes in succinate dehydrogenase (SDH), a TCA cycle enzyme with well‐known tumor suppressor activity. We show that AR directly regulates transcription of its catalytic subunits (SDHA, SDHB) via androgen response elements (AREs). ARPI acutely suppresses SDH activity, leading to accumulation of the oncometabolite, succinate. Succinate triggers calcium ions release from intracellular stores, which in turn phospho‐activates the AR‐cochaperone, Hsp27 via p‐CaMKK2/p‐AMPK/p‐p38 axis to enhance AR protein stabilization and activity. Activation of this pathway was seen in tissue microarray analysis on prostatectomy tissues and patient‐derived xenografts. This adaptive response is blocked by co‐targeting AR with Hsp27 under both in vitro and in vivo studies, sensitizing PCa cells to ARPI treatments. Synopsis: Prostate cancer becomes resistant to treatments targeting oncogenic androgen receptor (AR) via coordinated activity of multiple adaptive responses. This study defines metabolic reprogramming in response to AR pathway inhibition (ARPI) that supports AR reactivation. AR regulatory elements (AREs) were identified in catalytic subunits SDHA and SDHB of succinate dehydrogenase (SDH) enzyme.ARPI inhibited SDH activity resulting in accumulation of intracellular succinate.Intracellular succinate triggered Ca2+release to activate p‐CAMKK2/p‐AMPK/p‐p38 axis, increasing levels of the AR co‐chaperone p‐Hsp27 to support AR protein and signaling.Co‐targeting p‐Hsp27 with ARPI abrogated this succinate‐mediated adaptive loop and enhanced prostate cancer sensitivity to ARPI. [ABSTRACT FROM AUTHOR]

Although primary androgen deprivation therapy resulted in tumour regression, unfortunately, majority of prostate cancer progress to a lethal castration‐resistant prostate cancer, finally die to metastasis. The mutual feedback between AKT and AR pathways plays a vital role in the progression and metastasis of prostate cancer. Therefore, the treatment of a single factor will eventually inevitably lead to failure. Therefore, better understanding of the molecular mechanisms underlying metastasis is critical to the development of new and more effective therapeutic agents. In this study, we created prostate cancer CWR22rv1 cells with the double knockout of Akt1 and Akt2 genes through CRISPR/Cas9 method to investigate the effect of Akt in metastasis of prostate cancer. It was found that knockout of Akt1/2 resulted in markedly reduced metastasis in vitro and in vivo, and appeared to interfere AR nuclear translocation through regulating downstream regulatory factor, FOXO proteins. It suggests that some downstream regulatory factors in the AKT and AR interaction network play a vital role in prostate cancer metastasis and are potential targeting molecules for prostate cancer metastasis treatment. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) progression is driven by androgen receptor (AR) signaling. Unfortunately, androgen‐deprivation therapy and the use of even more potent AR pathway inhibitors (ARPIs) cannot bring about a cure. ARPI resistance (ie, castration‐resistant PCa, CRPC) will inevitably develop. Previously, we demonstrated that GRB10 is an AR transcriptionally repressed gene that functionally contributes to CRPC development and ARPI resistance. GRB10 expression is elevated prior to CRPC development in our patient‐derived xenograft models and is significantly upregulated in clinical CRPC samples. Here, we analyzed transcriptomic data from GRB10 knockdown in PCa cells and found that AR signaling is downregulated. While the mRNA expression of AR target genes decreased upon GRB10 knockdown, AR expression was not affected at the mRNA or protein level. We further found that phosphorylation of AR serine 81 (S81), which is critical for AR transcriptional activity, is decreased by GRB10 knockdown and increased by its overexpression. Luciferase assay using GRB10‐knockdown cells also indicate reduced AR activity. Immunoprecipitation coupled with mass spectrometry revealed an interaction between GRB10 and the PP2A complex, which is a known phosphatase of AR. Further validations and analyses showed that GRB10 binds to the PP2Ac catalytic subunit with its PH domain. Mechanistically, GRB10 knockdown increased PP2Ac protein stability, which in turn decreased AR S81 phosphorylation and reduced AR activity. Our findings indicate a reciprocal feedback between GRB10 and AR signaling, implying the importance of GRB10 in PCa progression. What's new? Androgen receptor (AR) signaling is the dominant driver of AR‐dependent castration‐resistant prostate cancer (CRPC) development and progression, even with continuous androgen deprivation therapy. The mechanisms causing the reactivation of AR signaling in CRPC remain unclear. Here, the authors demonstrate that the adaptor protein GRB10 sustains AR activity in CRPC. Data from high‐throughput proteomics analysis indicate that the reported tumor suppressor PP2A is a mediator of AR modulation by GRB10. GRB10 interacts with PP2A and promotes its degradation, thereby protecting phosphorylated AR from dephosphorylation and sustaining active AR signaling. Inhibiting GRB10 therapeutically could potentially improve CRPC management. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the most common malignancy and is the second leading cause of cancer among men globally. Using a kinome‐wide lentiviral small‐hairpin RNA (shRNA) library screen, we identified phosphoinositide‐dependent kinase‐1 (PDPK1) as a potential mediator of cell survival in PCa cells. We showed that knock‐down of endogenous human PDPK1 induced significant tumour‐specific cell death in PCa cells (DU145 and PC3) but not in the normal prostate epithelial cells (RWPE‐1). Further analyses revealed that PDPK1 mediates cancer cell survival predominantly via activation of serum/glucocorticoid‐regulated kinase 3 (SGK3). Knock‐down of endogenous PDPK1 in DU145 and PC3 cells significantly reduced SGK3 phosphorylation while ectopic expression of a constitutively active SGK3 completely abrogated the apoptosis induced by PDPK1. In contrast, no such effect was observed in SGK1 and AKT phosphorylation following PDPK1 knock‐down. Importantly, PDPK1 inhibitors (GSK2334470 and BX‐795) significantly reduced tumour‐specific cell growth and synergized docetaxel sensitivity in PCa cells. In summary, our results demonstrated that PDPK1 mediates PCa cells' survival through SGK3 signalling and suggest that inactivation of this PDPK1‐SGK3 axis may potentially serve as a novel therapeutic intervention for future treatment of PCa. [ABSTRACT FROM AUTHOR]

The human phosphatidylinositol 4‐phosphate 5‐kinase type I α (hPIP5K1α) participates in the phosphoinositide‐3‐kinase/protein kinase B/mammalian target of rapamycin signaling pathway. Despite the evidence that hPIP5K1α plays a role in the development of prostate cancer (PCa), only one inhibitor is known to date. With the aim of identifying new inhibitors, a nonradiometric assay for measurement of the hPIP5K1α enzyme activity was developed. The assay is based on the separation of the fluorescently labeled substrate phosphatidylinositol‐4‐phosphate (PI(4)P) and the resulting product phosphatidylinositol‐4,5‐bisphosphate (PIP2) by capillary electrophoresis (CE). Furthermore, an inactive mutant K261A of hPIP5K1α was generated by site‐directed mutagenesis and used as a control. Michaelis–Menten analysis revealed a Km value of 21.6 µm and Vmax of 0.65 pmol·min−1 for the cosubstrate ATP. The average Z' value was determined to be 0.86, indicating a high reliability of the assay. An in silico screening of an in‐house compound library was performed employing the crystal structure of zebrafish PIP5K1α. By applying this strategy, three compounds with a 2‐amino‐3‐cyano‐4H‐pyranobenzoquinone scaffold were identified and tested using the CE‐based assay. These compounds inhibited hPIP5K1α to > 90% at a concentration of 50 µm. Subsequently, the inhibitory activity of all compounds with a pyranobenzoquinone scaffold (29) was tested on hPIP5K1α. Compound 4‐(2‐amino‐3‐cyano‐6‐hydroxy‐5,8‐dioxo‐7‐undecyl‐5,8‐dihydro‐4H‐chromen‐4‐yl)benzoic acid appeared to be the most potent inhibitor of hPIP5K1α identified so far with an IC50 value of 1.55 µm, exhibiting a substrate‐competitive mode of action. The effects of this compound on cell viability and the induction of apoptosis were investigated in LNCaP, DU145, and PC3 PCa cells. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) has a broad spectrum of clinical behavior; hence, biomarkers are urgently needed for risk stratification. Here, we aim to find potential biomarkers for risk stratification, by utilizing a gene co‐expression network of transcriptomics data in addition to laser‐microdissected proteomics from human and murine prostate FFPE samples. We show up‐regulation of oxidative phosphorylation (OXPHOS) in PCa on the transcriptomic level and up‐regulation of the TCA cycle/OXPHOS on the proteomic level, which is inversely correlated to STAT3 expression. We hereby identify gene expression of pyruvate dehydrogenase kinase 4 (PDK4), a key regulator of the TCA cycle, as a promising independent prognostic marker in PCa. PDK4 predicts disease recurrence independent of diagnostic risk factors such as grading, staging, and PSA level. Therefore, low PDK4 is a promising marker for PCa with dismal prognosis. Synopsis: Transcriptomic and proteomic analyses in prostate cancer (PCa) reveal high TCA/OXPHOS activity and low PDK4 expression in low STAT3 tumors. PDK4 is a promising independent predictor of biochemical recurrence in PCa. Low STAT3 tumors show enhanced TCA/OXPHOS and ribosome activity in a gene co‐expression network and in transcriptomic and proteomic analyses.Enhanced ribosome‐ and metabolic activity is found in mice with a deletion of Pten and Stat3 in the prostate epithelium.Low STAT3 is associated with low PDK4 expression.PDK4 is an important regulator of TCA/OXPHOS. Analysis of patient data indicates that low PDK4 correlates with earlier biochemical recurrence in PCa. [ABSTRACT FROM AUTHOR]

Prostate adenocarcinoma (PCa) is the most common cause of death due to malignancy among men, and bone metastasis is the leading cause of mortality in patients with PCa. Therefore, identifying the causes and molecular mechanism of bone metastasis is important for early detection, diagnosis and personalized therapy. In this study, we systematically analyzed molecular correlates of bone metastasis by bioinformatics analysis. A total of 12 differentially expressed microRNAs (miRNAs) and 102 differentially expressed genes were identified. Five miRNAs had prognostic significance in biochemical recurrence‐free survival (miR‐636, miR‐491‐5p, miR‐199b‐5p, miR‐199b‐3p, miR‐28‐3p). The differentially expressed genes were significantly enriched in extracellular matrix, cell‐substrate adhesion, collagen and integrin. Seven hub genes (VCAN, COL3A1, COL1A1, APOE, COL1A2, SDC1, THY1) with worse biochemical recurrence‐free survival and one hub gene (MMP9) with worse overall survival were detected. miR‐636, a novel oncogene, was found to be up‐regulated in bone metastatic PCa tissues and also predominately up‐regulated in human PCa cell lines. miR‐636 promoted cellular invasion and migration, and may promote bone metastasis via targeting MBNL2, TNS1 and STAB1. In conclusion, we have successfully defined molecular signatures of bone metastasis in PCa. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the most prevalent cancer among men and the second leading cause of tumor‐associated deaths worldwide, with increasing incidence rates over the last 10 years. Recently, miR‐195 was reported to be hypermethylated at its promoter CpG island and down‐regulated in hepatocellular carcinoma. However, the function of miR‐195 and the underlying mechanisms in PCa remain unknown. Here, we report that a significant down‐regulation of microRNA‐195 (miR‐195) in PCa tissues and cell lines was associated with promoter methylation status. Overexpression of miR‐195 significantly suppressed cell proliferation, migration, invasion and epithelial–mesenchymal transition (increased E‐cadherin and decreased N‐cadherin) in PCa cells. We further demonstrated that transfection with a miR‐195 inhibitor reversed the inhibitory effect of the DNA methyltransferase inhibitor 5‐azacytidine on the proliferation, migration and invasion ability of PCa cells. In summary, our findings suggest that miR‐195 may function as a crucial tumor suppressor in PCa. [ABSTRACT FROM AUTHOR]

Background: A high prevalence of osteoblastic bone metastases is characteristic of prostate cancer. Prostate‐specific antigen (PSA) is a serine protease uniquely produced by prostate cancer cells and is an important serological marker for prostate cancer. However, whether PSA modulates the osteogenic process remains largely unknown. In this study, we explored the effect of PSA on modulating the osteoblastic differentiation of mesenchymal stem cells (MSCs). In this study, we used flow cytometry, CCK‐8 assay, Alizarin red S (ARS) staining and quantification, alkaline phosphatase (ALP) activity and staining, Western blotting, and quantitative real‐time PCR (qRT‐PCR) to explore the effect of PSA on osteogenic differentiation of MSCs. Results: We first demonstrated that although PSA did not affect the proliferation, morphology, or phenotype of MSCs, it significantly promoted the osteogenic differentiation of MSCs in a concentration‐dependent manner. Furthermore, we demonstrated that PSA promoted the osteogenic differentiation of MSCs by elevating the expression of Cadherin 11 in MSCs and, thus, activating the Akt signaling pathway. Conclusions: In conclusion, we demonstrated that PSA could promote the osteogenesis of MSCs through Akt signaling pathway activation by elevating the expression of cadherin‐11 in MSCs. These findings imply a possible role of PSA in osteoblastic bone metastases in prostate cancer. [ABSTRACT FROM AUTHOR]

The Mediator complex is a transcriptional regulator interacting with transcription factors and RNA‐polymerase‐II. Recently, we identified its subunit CDK19 to be specifically expressed in prostate cancer (PCa) and to be functionally implicated in PCa aggressiveness. Aim of our study was to comprehensively characterize the protein expression of CDK19 and its paralog CDK8 in PCa. We performed immunohistochemistry (IHC) for CDK19/CDK8 on a large cohort including needle biopsies from 202 patients, 799 primary tumor foci of radical prostatectomy specimens from 415 patients, 120 locally advanced tumor foci obtained by palliative transurethral resection, 140 lymph node metastases, 67 distant metastases and 82 benigns. Primary tumors were stained for the proliferation marker Ki67, androgen receptor (AR) and ERG. For 376 patients, clinic–pathologic data were available. Primary endpoint was disease‐recurrence‐free survival (DFS). Nuclear CDK19 and CDK8 expression increases during progression showing the highest intensity in metastatic and castration‐resistant tumors. High CDK19 expression on primary tumors correlates with DFS independently from Gleason grade and PSA. Five‐year‐DFS rates of patients with primary tumors expressing no, moderate and high CDK19 are 73.7, 56.9 and 30.4%, respectively. CDK19 correlates with Gleason grade, T‐stage, Ki67 proliferation‐index, nuclear AR expression and ERG‐status. Therapeutic options for metastatic and castration‐resistant PCa remain limited. In the current study, we confirmed an important role of the Mediator subunit CDK19 in advanced PCa supporting current developments to target CDK19 and its paralog CDK8. Furthermore, CDK19 protein expression has the potential to predict disease recurrence independently from established biomarkers thus contributing to individual management for PCa patients. What's new? The Mediator complex is a highly conserved protein complex, consisting of 33 subunits, which regulates DNA transcription. Several subunits of the Mediator complex have been associated with cancer subtypes. Here, the authors investigated the role of Mediator subunit CDK19, and its paralog CDK8, in prostate cancer. They performed immunohistochemistry on 1,208 tissue samples to compare the expression levels of the two proteins in different patients. CDK19 and CDK8 expression appears to increase over the course of disease progression, with metastatic and castration‐resistant disease showing the highest levels. They found that CDK19 expression predicted disease aggressiveness and recurrence. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is one of the most common types of cancer in men. In several recent studies, chromosomal deletions in the q arm of chromosome 2, where ING5 resides within, have been identified in various cancer types including PCa. In this study, we investigate the role of ING5 as a tumor suppressor in PCa. We examined the expression level of ING5 in tissue samples and cell lines using quantitative real‐time polymerase chain reaction and western blot analysis. We tested the in vitro tumor suppressor potential of ING5 in PC3 and LNCaP cells stably overexpressing it using cell viability, colony formation, migration, invasion, and apoptosis assays. We then investigated the effects of ING5 on the Akt and p53 signaling using western blot analysis. We show that ING5 is significantly downregulated in PCa tumor tissue samples and cell lines compared with the corresponding controls. In vitro assays demonstrate that ING5 effectively suppresses proliferative, clonogenic, migratory, and invasive potential and induce apoptosis in PCa cells. ING5 may potentially exert its anti‐tumor potential by inhibiting AKT and inducing p53 signaling pathways. Our findings demonstrate that ING5 possesses tumor suppressor roles in vitro, pointing its importance during the prostatic carcinogenesis processes. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the most common cancer diagnosed and the second most common cause of cancer‐related death in men worldwide. The current androgen deprivation therapy for PCa cannot fully cure this disease. Moreover, androgen receptor gene amplification and mutation are associated with PCa to develop castration‐resistant prostate cancer (CRPC). This review focuses on the deubiquitinases (DUBs) involved in PCa development and progression. For PCa development and progression, several cellular pathways are regulated by specific DUBs which are also highlighted in here. The ubiquitin‐specific proteases (USPs), a family member of DUBs mostly involved in the regulation of cellular pathways for PCa development, and the ubiquitin C‐terminal hydrolases (UCHs), another family member of DUBs, are responsible for PCa metastasis. Small molecular inhibitors against DUBs can inhibit or reduce the level of specific DUBs through the regulation of cellular pathway to treat this disease. Some small molecular inhibitors are already identified against some of the DUBs, but very few of them are clinically proved in PCa. So, to find out other DUBs involving in the regulation of PCa‐related pathways and to develop more effective small molecule inhibitors with greater potency would be a great idea to target PCa cells for future therapeutics and drug development with or without the combination of other anticancer drugs. Significance of the study: This review is targeting DUB proteins which are responsible for PCa induction, proliferation, and metastasis by highlighting their signalling pathway so that the readers can get information about other mechanisms for PCa besides androgen receptor pathway and helps to find other oncogenic DUBs involving in these signalling pathways. This review also hopes to find other oncogenic DUBs involving in PCa‐related signalling pathways or to find the DUBs that can regulate multiple oncogenic signalling pathways which might be a good target for PCa therapeutics. In addition, there are some small molecule inhibitors that can inhibit the oncogenic DUBs and thus able to control the oncogenic pathways which would be a novel strategy to treat CRPC by using DUB inhibitor combined with or without other anticancer drugs. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the second most common cause of cancer‐related mortality in men in the United States. The androgen receptor (AR) and the physiological pathways it regulates are central to the initiation and progression of PCa. As a member of the nuclear steroid receptor family, it is a transcription factor with three distinct functional domains (ligand‐binding domain [LBD], DNA‐binding domain [DBD], and transactivation domain [TAD]) in its structure. All clinically approved drugs for PCa ultimately target the AR‐LBD. Clinically active drugs that target the DBD and TAD have not yet been developed due to multiple factors. Despite these limitations, the last several years have seen a rise in the discovery of molecules that could successfully target these domains. This review aims to present and comprehensively discuss such molecules that affect AR signaling through direct or indirect interactions with the AR‐TAD or the DBD. The compounds discussed here include hairpin polyamides, niclosamide, marine sponge–derived small molecules (eg, EPI compounds), mahanine, VPC compounds, JN compounds, and bromodomain and extraterminal domain inhibitors. We highlight the significant in vitro and in vivo data found for each compound and the apparent limitations and/or potential for further development of these agents as PCa therapies. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study is to evaluate the use of androgen deprivation therapy (ADT) with post-prostatectomy radiotherapy (PPRT) in a population-based cohort of Australian men.Methods: This is a prospective cohort of men with localised prostate cancer captured in the Prostate Cancer Outcomes Registry Victoria (PCOR-Vic), who received PPRT between January 2010 and December 2015. The primary outcome was ADT use with PPRT. Multivariate logistic regressions were used to identify patient, tumour and institutional factors influencing ADT use.Results: 485 men were included in this study - 115 (24%) had pT2 disease, 231 (48%) pT3a, 134 (28%) pT3b and 5 (1%) pT4. Eighteen (4%) men had ISUP grade 1 disease, 139 (29%) ISUP grade 2, 170 (35%) ISUP grade 3 and 158 (33%) ISUP grade 4/5, while 267 (64%) men had positive surgical margins. Median time from prostatectomy to PPRT was 8.1 months (IQR = 5.3-13.9). Sixty-six (14%) patients had ADT with PPRT. In multivariate analyses, men who had increased age (OR = 1.06; 95% CI = 1.01-1.11), seminal vesicle involvement (OR = 3.81; 95% CI = 1.63-8.91) and underwent treatment in regional centres (OR = 2.17; 95% CI = 1.08-4.33) were more likely to have ADT with PPRT.Conclusion: We reported that 14% of men treated with PPRT received ADT in a population-based cohort of Australian men, which was less than half of the proportion of ADT use with PPRT in the US. It will be of interest to evaluate the uptake of ADT with PPRT in the coming years following recent publications of level 1 evidence confirming overall survival benefits of ADT with PPRT. [ABSTRACT FROM AUTHOR]

Background: Men with locally advanced prostate cancer (LAPCa) or regionally advanced prostate cancer (RAPCa) are at high risk for death from their disease. Clinical guidelines support multimodal approaches, which include radical prostatectomy (RP) followed by radiotherapy (XRT) and XRT plus androgen deprivation therapy (ADT). However, there are limited data comparing these substantially different treatment approaches. Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, this study compared survival outcomes and adverse effects associated with RP plus XRT versus XRT plus ADT in these men.Methods: SEER-Medicare data were queried for men with cT3-T4N0M0 (LAPCa) or cT3-T4N1M0 (RAPCa) prostate cancer. Propensity score methods were used to balance cohort characteristics between the treatment arms. Survival analyses were analyzed with the Kaplan-Meier method and Cox proportional hazards models.Results: From 1992 to 2009, 13,856 men (≥65 years old) were diagnosed with LAPCa or RAPCa: 6.1% received RP plus XRT, and 23.6% received XRT plus ADT. At a median follow-up of 14.6 years, there were 2189 deaths in the cohort, of which 702 were secondary to prostate cancer. Regardless of the tumor stage or the Gleason score, the adjusted 10-year prostate cancer-specific survival and 10-year overall survival favored men who underwent RP plus XRT over men who underwent XRT plus ADT. However, RP plus XRT versus XRT plus ADT was associated with higher rates of erectile dysfunction (28% vs 20%; P = .0212) and urinary incontinence (49% vs 19%; P < .001).Conclusions: Men with LAPCa or RAPCa treated initially with RP plus XRT had a lower risk of prostate cancer-specific death and improved overall survival in comparison with those men treated with XRT plus ADT, but they experienced higher rates of erectile dysfunction and urinary incontinence. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the most common form of cancer in men in the developed world and the second leading cause of cancer‐related deaths. While advanced PCa is initially controlled with hormonal therapies targeting the androgen receptor (AR) pathway, recurrence occurs because of the emergence of lethal castration‐resistant PCa (CRPC). Despite newer AR pathway inhibitors that prolong survival, resistance still emerges, most often with rising PSA levels indicative of AR‐driven activity, but increasingly as non‐AR‐driven cancer. Treatment resistance mechanisms include AR‐signalling pathway alterations, AR‐signalling bypass mechanisms, and AR‐independent clonal evolution. The latter mechanism can lead to the emergence of neuroendocrine prostate cancer (NEPC), an aggressive lethal subtype of PCa. The incidence of treatment‐induced NEPC is rising because of the widespread use of more potent AR pathway inhibitors. This comprehensive review of major NEPC drivers and facilitators defines three coordinated processes contributing to NEPC progression. Specifically, castration‐resistant adenocarcinoma cells gain lineage plasticity under selective pressures of potent AR suppression to transform into AR‐independent tumour cells. In concert, neuroendocrine (NE)‐specific transdifferentiation factors induce NE lineage of these PCa cells, which, with support of increased proliferation factors, contributes to clonal expansion and tumour repopulation into NEPC. We examine the roles of each of the major NEPC contributors during the disease progression and identify potential therapeutic opportunities for targeted therapies. [ABSTRACT FROM AUTHOR]

Abstract: Background: We evaluated the association between serum levels of insulin‐like growth factor‐1 (IGF‐1), bioavailable testosterone, and surgical Gleason score (GS). Methods: We analyzed 793 patients who underwent radical prostatectomy and 272 men with negative prostate biopsy. Serum levels of IGF‐1 and testosterone were measured before surgery or biopsy. Results: The mean IGF‐1 levels of prostate cancer patients and men with a negative biopsy were 143.8 and 118.9 ng/mL, respectively (P < 0.001). Men with high serum IGF‐1 were more likely to have prostate cancer (highest vs lowest quartile, odds ratio [OR] = 3.35; Ptrend < 0.001). However, among men with prostate cancer, the mean IGF‐1 levels of those with low (GS ≤ 6), intermediate (GS = 7), and high surgical GS (GS ≥8) were 151.7, 144.1, and 132.9 ng/mL, respectively (P < 0.001). Using quartile analysis, high serum IGF‐1 levels were shown to be associated with a low risk of high surgical GS (OR = 0.464; Ptrend = 0.006). Serum bioavailable testosterone concentration was positively correlated with serum IGF‐1 level (r = 0.157, P < 0.001). High bioavailable testosterone level was also associated with a low risk of high surgical GS in patients without diabetes mellitus (OR = 0.569; Ptrend = 0.040). Among men with biopsy GS ≤ 3 + 4 (n = 460), upgrading to high surgical GS was more frequent in patients with low IGF‐1 level (≤116.0 ng/mL; 9.9%) or low bioavailable testosterone level (≤0.85 ng/mL; 9.3%) than in patients with normal IGF‐1 and bioavailable testosterone levels (2.6%; P = 0.004). Conclusions: Serum levels of IGF‐1 and bioavailable testosterone show inverse associations with high surgical GS. This suggests that high‐grade prostate cancer develops independently of these two substances. [ABSTRACT FROM AUTHOR]

Abstract: To exploit vulnerabilities of tumors, it is urgent to identify associated defects in genome maintenance. One unsolved problem is the mechanism of regulation of DNA double‐strand break repair by REV7 in complex with 53BP1 and RIF1, and its influence on repair pathway choice between homologous recombination and non‐homologous end‐joining. We searched for REV7‐associated factors in human cells and found FAM35A, a previously unstudied protein with an unstructured N‐terminal region and a C‐terminal region harboring three OB‐fold domains similar to single‐stranded DNA‐binding protein RPA, as novel interactor of REV7/RIF1/53BP1. FAM35A re‐localized in damaged cell nuclei, and its knockdown caused sensitivity to DNA‐damaging agents. In a BRCA1‐mutant cell line, however, depletion of FAM35A increased resistance to camptothecin, suggesting that FAM35A participates in processing of DNA ends to allow more efficient DNA repair. We found FAM35A absent in one widely used BRCA1‐mutant cancer cell line (HCC1937) with anomalous resistance to PARP inhibitors. A survey of FAM35A alterations revealed that the gene is altered at the highest frequency in prostate cancers (up to 13%) and significantly less expressed in metastatic cases, revealing promise for FAM35A as a therapeutically relevant cancer marker. [ABSTRACT FROM AUTHOR]

Most patients with prostate cancer will eventually develop the castration‐resistant form characterised by metastasis. Cytoskeleton constituents, including F‐actin, play important roles in maintaining epithelial integrity and their disruption is a major cause of cancer progression. We previously showed that scinderin (SCIN), an important regulator of F‐actin organisation, is highly expressed in poorly differentiated cancer tissues. This study aimed to explore the mechanism of its regulation of cell proliferation. We discovered that SCIN knockdown significantly downregulated epidermal growth factor receptor (EGFR) protein expression, and inhibited epidermal growth factor (EGF)‐mediated cell proliferation and activation of the downstream mitogen‐activated protein kinase kinase (MEK)/extracellular signal‐regulated kinase (ERK) signalling pathway. Silencing of SCIN promoted apoptosis in two cell lines (PC‐3 and DU145), inhibited B‐cell lymphoma‐extra‐large (Bcl‐xl) expression and activated caspase signalling. Furthermore, in vivo studies showed that SCIN deletion slowed tumour growth and decreased EGFR expression. Thus, we conclude that SCIN promotes prostate cancer cell survival by stabilising EGFR and MEK/ERK signalling. [ABSTRACT FROM AUTHOR]

Abstract: Metastatic castration‐resistant prostate cancer (mCRPC) is a lethal form of treatment‐resistant prostate cancer and poses significant therapeutic challenges. Deregulated receptor tyrosine kinase (RTK) signalling mediated by loss of tumour suppressor Sprouty2 (SPRY2) is associated with treatment resistance. Using pre‐clinical human and murine mCRPC models, we show that SPRY2 deficiency leads to an androgen self‐sufficient form of CRPC. Mechanistically, HER2‐IL6 signalling axis enhances the expression of androgen biosynthetic enzyme HSD3B1 and increases SRB1‐mediated cholesterol uptake in SPRY2‐deficient tumours. Systemically, IL6 elevated the levels of circulating cholesterol by inducing host adipose lipolysis and hepatic cholesterol biosynthesis. SPRY2‐deficient CRPC is dependent on cholesterol bioavailability and SRB1‐mediated tumoral cholesterol uptake for androgen biosynthesis. Importantly, treatment with ITX5061, a clinically safe SRB1 antagonist, decreased treatment resistance. Our results indicate that cholesterol transport blockade may be effective against SPRY2‐deficient CRPC. [ABSTRACT FROM AUTHOR]

Abstract: AKT‐mTOR and androgen receptor (AR) signaling pathways are aberrantly activated in prostate cancer due to frequent PTEN deletions or SPOP mutations. A clinical barrier is that targeting one of them often activates the other. Here, we demonstrate that HDAC3 augments AKT phosphorylation in prostate cancer cells and its overexpression correlates with AKT phosphorylation in patient samples. HDAC3 facilitates lysine‐63‐chain polyubiquitination and phosphorylation of AKT, and this effect is mediated by AKT deacetylation at lysine 14 and 20 residues and HDAC3 interaction with the scaffold protein APPL1. Conditional homozygous deletion of Hdac3 suppresses prostate tumorigenesis and progression by concomitant blockade of AKT and AR signaling in the Pten knockout mouse model. Pharmacological inhibition of HDAC3 using a selective HDAC3 inhibitor RGFP966 inhibits growth of both PTEN‐deficient and SPOP‐mutated prostate cancer cells in culture, patient‐derived organoids and xenografts in mice. Our study identifies HDAC3 as a common upstream activator of AKT and AR signaling and reveals that dual inhibition of AKT and AR pathways is achievable by single‐agent targeting of HDAC3 in prostate cancer. [ABSTRACT FROM AUTHOR]

Genetically engineered mouse models of cancer can be used to filter genome-wide expression datasets generated from human tumours and to identify gene expression alterations that are functionally important to cancer development and progression. In this study, we have generated RNAseq data from tumours arising in two established mouse models of prostate cancer, PB-Cre/PtenloxP/loxP and p53loxP/loxPRbloxP/loxP, and integrated this with published human prostate cancer expression data to pinpoint cancer-associated gene expression changes that are conserved between the two species. To identify potential therapeutic targets, we then filtered this information for genes that are either known or predicted to be druggable. Using this approach, we revealed a functional role for the kinase MELK as a driver and potential therapeutic target in prostate cancer. We found that MELK expression was required for cell survival, affected the expression of genes associated with prostate cancer progression and was associated with biochemical recurrence. [ABSTRACT FROM AUTHOR]

Abstract: Locally advanced prostate cancer is regarded as a very high‐risk disease with a poor prognosis. Although there is no definitive consensus on the definition of locally advanced prostate cancer, radical prostatectomy for locally advanced prostate cancer as a primary treatment or part of a multimodal therapy has been reported. Robot‐assisted radical prostatectomy is currently carried out even in high‐risk prostate cancer because it provides optimal outcomes. However, limited studies have assessed the role of robot‐assisted radical prostatectomy in patients with locally advanced prostate cancer. Herein, we summarize and review the current knowledge in terms of the definition and surgical indications of locally advanced prostate cancer, and the surgical procedure and perisurgical/oncological outcomes of robot‐assisted radical prostatectomy and extended pelvic lymphadenectomy for locally advanced prostate cancer. [ABSTRACT FROM AUTHOR]

publisher‐imprint‐name Springer volume‐issue‐count 1 issue‐article‐count 0 issue‐toc‐levels 0 issue‐pricelist‐year 2017 issue‐copyright‐holder The Author(s) issue‐copyright‐year 2017 article‐contains‐esm No article‐numbering‐style Unnumbered article‐registration‐date‐year 2017 article‐registration‐date‐month 2 article‐registration‐date‐day 6 article‐toc‐levels 0 toc‐levels 0 volume‐type Regular journal‐product ArchiveJournal numbering‐style Unnumbered article‐grants‐type OpenChoice metadata‐grant OpenAccess abstract‐grant OpenAccess bodypdf‐grant OpenAccess bodyhtml‐grant OpenAccess bibliography‐grant OpenAccess esm‐grant OpenAccess online‐first false pdf‐file‐reference BodyRef/PDF/40169_2017_Article_138.pdf target‐type OnlinePDF issue‐type Regular article‐type Letter journal‐subject‐primary Medicine & Public Health journal‐subject‐secondary Medicine/Public Health, general journal‐subject‐collection SC11 --> Phosphoproteomic analysis of tumor samples has the potential to uncover significant insights into kinase signaling networks present in late stage prostate cancer that are complementary to genomic and transcriptomic approaches. Phosphoproteomics could potentially aid drug development in clinical trial design as well as provide utility for oncologists in the personalized therapeutic management of individual cancers through identifying novel biomarkers and druggable targets. Rapid advancement of targeted mass spectrometry platforms is underway to integrate phosphoproteomic technology with genomic assays to soon translate this information into the cancer clinic. [ABSTRACT FROM AUTHOR]

Abstract: Aberrant phosphoinositide 3‐kinase (PI3K), mitogen‐activated protein kinase (MAPK) and WNT signalling are emerging as key events in the multistep nature of prostate tumourigenesis and progression. Here, we report a compound prostate cancer murine model in which these signalling pathways cooperate to produce a more aggressive prostate cancer phenotype. Using Cre‐LoxP technology and the probasin promoter, we combined the loss of Pten (Ptenfl/fl), to activate the PI3K signalling pathway, with either dominant stabilized β‐catenin [Catnb+/lox(ex3)] or activated K‐RAS (K‐Ras+/V12) to aberrantly activate WNT and MAPK signalling, respectively. Synchronous activation of all three pathways (triple mutants) significantly reduced survival (median 96 days) as compared with double mutants [median: 140 days for Catnb+/lox(ex3)Ptenfl/fl; 182 days for Catnb+/lox(ex3)K‐Ras+/V12; 238 days for Ptenfl/flK‐Ras+/V12], and single mutants [median: 383 days for Catnb+/lox(ex3); 407 days for Ptenfl/fl], reflecting the accelerated tumourigenesis. Tumours followed a stepwise progression from mouse prostate intraepithelial neoplasia to invasive adenocarcinoma, similar to that seen in human disease. There was significantly elevated cellular proliferation, tumour growth and percentage of invasive adenocarcinoma in triple mutants as compared with double mutants and single mutants. Triple mutants showed not only activated AKT, extracellular‐signal regulated kinase 1/2, and nuclear β‐catenin, but also significantly elevated signalling through mechanistic target of rapamycin complex 1 (mTORC1). In summary, we show that combined deregulation of the PI3K, MAPK and WNT signalling pathways drives rapid progression of prostate tumourigenesis, and that deregulation of all three pathways results in tumours showing aberrant mTORC1 signalling. As mTORC1 signalling is emerging as a key driver of androgen deprivation therapy resistance, our findings are important for understanding the biology of therapy‐resistant prostate cancer and identifying potential approaches to overcome this. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Cancer has been mainly treated by traditional therapeutic approaches which do not consider the human genetic diversity and present limitations, probably as a consequence of a poor knowledge of both patient's genetic background and tumor biology. Due to genome project conclusion and large-scale gene analyses emergence, the therapeutic management of several prevalent and aggressive tumors has dramatically improved and represents the closest examples of a precision medicine intervention in this field. Nonetheless, prostate cancer (PCa) remains as a challenge to personalized medicine implementation, probably due to its notorious heterogeneous molecular profile. Cancer treatment personalized approaches rely on the premise that a well-defined panorama of tumor molecular alterations can help selecting new and specific therapeutic targets for its treatment and potentially discriminate tumors which behave differentially. Lately, molecular and genetic studies have been investigating PCa basis, revealing multiple recurrent genomic alterations that include mutations, DNA copy-number variations, rearrangements, and gene fusions, among others. In addition to the increment on PCa molecular biology knowledge, mapping the molecular alterations pattern of this neoplasia, especially the differences existent between tumors displaying distinct behaviors, could represent a great improvement concerning the identification of new targets, personalized medicine, and patients' management and prognosis. [ABSTRACT FROM AUTHOR]

Castration-resistant prostate cancer is a lethal disease. The cell type(s) that survive androgen deprivation remain poorly described, despite global efforts to understand the various mechanisms of therapy resistance. We recently identified in wild-type (WT) mouse prostates a rare population of luminal progenitor cells that we called LSCmed according to their FACS profile (Lin−/Sca-1+/CD49fmed). Here, we investigated the prevalence and castration resistance of LSCmed in various mouse models of prostate tumourigenesis (Pb-PRL, Pten pc−/−, and Hi-Myc mice). LSCmed prevalence is low (∼8%, similar to WT) in Hi-Myc mice, where prostatic androgen receptor signalling is unaltered, but is significantly higher in the two other models, where androgen receptor signalling is decreased, rising up to more than 80% in Pten pc−/− prostates. LSCmed tolerate androgen deprivation and persist or are enriched 2-3 weeks after castration. The tumour-initiating properties of LSCmed from Pten pc−/− mice were demonstrated by regeneration of tumours in vivo. Transcriptomic analysis revealed that LSCmed represent a unique cell entity as their gene expression profile is different from luminal and basal/stem cells, but shares markers of each. Their intrinsic androgen signalling is markedly decreased, explaining why LSCmed tolerate androgen deprivation. This also illuminates why Pten pc−/− tumours are castration-resistant since LSCmed represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSCmed on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSCmed in various mouse prostate specimens. In castrated Pten pc−/− prostates, there was significant proliferation of CK4+ cells, further demonstrating their key role in castration-resistant prostate cancer progression. Taken together, this study identifies LSCmed as a probable source of prostate cancer relapse after androgen deprivation and as a new therapeutic target for the prevention of castrate-resistant prostate cancer. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Metastatic disease is the leading cause of death due to prostate cancer (PCa). Although the hypermethylated in cancer 1 (HIC1) gene has been observed to be epigenetically modified in PCa, its intrinsic role and mechanism in PCa metastasis still remain uncertain. Here, we show that hypermethylation of the HIC1 promoter markedly reduces its suppressive function in metastatic PCa tissues as compared with primary and adjacent normal prostate tissues, and is associated with poor patient survival. PCas in cancer-prone mice homozygous for a prostate-targeted Hic1 conditional knockout showed stronger metastatic behaviour than those in heterozygous mice, as a result of epithelial-mesenchymal transition (EMT). Moreover, impairment of HIC1 expression in PCa cells induced their migration and metastasis through EMT, by enhancing expression of Slug and CXCR4, both of which are critical to PCa metastasis; the CXCL12-CXCR4 axis promotes EMT by activating the extracellular signal-regulated kinase (ERK) 1/2 pathway. Taken together, our results suggest that evaluation of HIC1-CXCR4-Slug signalling may provide a potential predictor for PCa aggressiveness. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Phosphoproteomic analysis of tumor samples has the potential to uncover significant insights into kinase signaling networks present in late stage prostate cancer that are complementary to genomic and transcriptomic approaches. Phosphoproteomics could potentially aid drug development in clinical trial design as well as provide utility for oncologists in the personalized therapeutic management of individual cancers through identifying novel biomarkers and druggable targets. Rapid advancement of targeted mass spectrometry platforms is underway to integrate phosphoproteomic technology with genomic assays to soon translate this information into the cancer clinic. [ABSTRACT FROM AUTHOR]

The androgen receptor is a transcription factor and validated therapeutic target for prostate cancer. Androgen deprivation therapy remains the gold standard treatment, but it is not curative, and eventually the disease will return as lethal castration-resistant prostate cancer. There have been improvements in the therapeutic landscape with new agents approved, such as abiraterone acetate, enzalutamide, sipuleucel-T, cabazitaxel and Ra-223, in the past 5 years. New insight into the mechanisms of resistance to treatments in advanced disease is being and has been elucidated. All current androgen receptor-targeting therapies inhibit the growth of prostate cancer by blocking the ligand-binding domain, where androgen binds to activate the receptor. Persuasive evidence supports the concept that constitutively active androgen receptor splice variants lacking the ligand-binding domain are one of the resistant mechanisms underlying advanced disease. Transcriptional activity of the androgen receptor requires a functional AF-1 region in its N-terminal domain. Preclinical evidence proved that this domain is a druggable target to forecast a potential paradigm shift in the management of advanced prostate cancer. This review presents an overview of androgen receptor-related mechanisms of resistance as well as novel therapeutic agents to overcome resistance that is linked to the expression of androgen receptor splice variants in castration-resistant prostate cancer. [ABSTRACT FROM AUTHOR]

Androgen deprivation therapy is the initial treatment for men with advanced prostate cancer. Almost all these patients eventually develop progressive castration-resistant prostate cancer despite an initial favorable response. Docetaxel was the first agent to show a survival benefit in patients with castration-resistant prostate cancer. After cancer progression on docetaxel, patients with castration-resistant prostate cancer had few therapeutic options. A better understanding of the mechanisms of resistance to androgen deprivation therapy has led to the development of novel agents with distinct mechanisms of action. Prospective, large-scale clinical trials have shown overall survival benefits with the hormonal agents abiraterone acetate and enzalutamide, the immunotherapeutic agent sipuleucel T, the chemotherapeutic agent cabazitaxel, and bone-targeted Ra-223. Although these agents provided clinical benefit, treatment for castration-resistant prostate cancer remains a major clinical challenge. We recognize many questions, such as methods to select patients for specific treatments, optimal sequencing and drug combinations, and means to overcome drug resistance. There is an urgent need to answer these questions and to establish better treatment strategies. The development of biomarkers that are predictive of treatment results is also required. The present article reviews new castration-resistant prostate cancer treatments, and discusses possible resistant mechanisms as well as potential drug combinations and optimal sequencing. [ABSTRACT FROM AUTHOR]

Genome-wide association studies have identified genomic loci, whose single-nucleotide polymorphisms (SNPs) predispose to prostate cancer (PCa). However, the mechanisms of most of these variants are largely unknown. We integrated chromatinimmunoprecipitation-coupled sequencing and microarray expression profiling in TMPRSS2-ERG gene rearrangement positive DUCaP cells with the GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor-binding sites (ARBSs). Among the 48 GWAS index risk SNPs and 3,917 linked SNPs, 80 were found located in ARBSs. Of these, rs11891426:T>G in an intron of the melanophilin gene (MLPH) was within a novel putative auxiliary ARbinding motif, which is enriched in the neighborhood of canonical androgen-responsive elements. T→G exchange attenuated the transcriptional activity of the ARBS in an AR reporter gene assay. The expression of MLPH in primary prostate tumors was significantly lower in those with the G compared with the T allele and correlated significantly with AR protein. Higher melanophilin level in prostate tissue of patients with a favorable PCa risk profile points out a tumor-suppressive effect. These results unravel a hidden link between AR and a functional putative PCa risk SNP, whose allele alteration affects androgen regulation of its host gene MLPH. [ABSTRACT FROM AUTHOR]

Purpose To identify the ability of multiple variables to predict prostate cancer specific mortality ( PCSM) in a whole of population series of all radical prostatectomies ( RP) performed in Victoria, Australia. Materials & Methods A total of 2154 open RPs were performed in Victoria between July 1995 and December 2000. Subjects without follow up data, Gleason grade, pathological stage were excluded as were those who had pT4 disease or received neoadjuvant treatment. 1967 cases (91.3% of total) met the inclusion criteria for this study. Tumour characteristics were collated via a central registry. We used competing hazards regression models to investigate associations. Results At median follow up of 10.3 years pT stage of RP ( P < 0.001) and high Gleason score of the RP specimen ( P < 0.001 for ≥8 [Subhazard ratio ( SHR) 11.19] and 4 + 3 = 7 [ SHR 7.10]) compared with Gleason score 6 disease were strong predictors of progression to PCSM. Gleason score 3 + 4 = 7 was not at this time a significant predictor of PCSM ( P = 0.08, SHR 1.84). Predictors of PCSM, independent of stage and grade, included rural residency ( P = 0.003), primary surgeon contributing less than 40 cases (low-volume) to the VRPR ( P = 0.025) and the involvement of a trainee surgeon in the operation ( P = 0.031). Conclusion The significant prediction of PCSM by pT cancer stage, Gleason score and primary Gleason pattern at RP in this whole of population study suggests a need to avoid understaging/grading in the process of cancer diagnosis and active surveillance protocols. Multi-modality therapy is likely to have a greater impact on PCSM in higher stage and Gleason grade disease. Identification of increased PCSM with rural residency and with involvement of a trainee urologist, and reduction in PCSM with higher surgeon volume all suggest potential for improved PC outcomes to be achieved with changes to surgical training and service delivery. [ABSTRACT FROM AUTHOR]

Dysregulated expression and/or mutations of the various components of the phosphoinositide 3-kinase (PI3K)/Akt pathway occur with high frequency in prostate cancer and are associated with the development and progression of castration resistant tumors. However, small molecule kinase inhibitors that target this signaling pathway have limited efficacy in inhibiting tumor growth, primarily due to compensatory survival signals through receptor tyrosine kinases (RTKs). Although members of the epidermal growth factor receptor (EGFR), or HER, family of RTKs are strongly implicated in the development and progression of prostate cancer, targeting individual members of this family such as EGFR or HER2 has resulted in limited success in clinical trials. Multiple studies indicate a critical role for HER3 in the development of resistance against both HER-targeted therapies and PI3K/Akt pathway inhibitors. In this study, we found that the growth inhibitory effect of GDC-0941, a class I PI3K inhibitor, is markedly reduced in the presence of heregulin. Interestingly, this effect is more pronounced in cells lacking phosphatase and tensin homolog function. Heregulin-mediated resistance to GDC-0941 is associated with reactivation of Akt downstream of HER3 phosphorylation. Importantly, combined blockade of HER2 and HER3 signaling by an anti-HER2/HER3 bispecific antibody or a mixture of anti-HER2 and anti-HER3 antibodies restores sensitivity to GDC-0941 in heregulin-treated androgen-dependent and -independent prostate cancer cells. These studies indicate that the combination of PI3K inhibitors with HER2/HER3 targeting antibodies may constitute a promising therapeutic strategy for prostate cancer. [ABSTRACT FROM AUTHOR]