Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate.
Ontology highlight
ABSTRACT:
SUBMITTER: Carver BS
PROVIDER: S-EPMC2835150 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Farnesyl diphosphate synthase (FDPS), a mevalonate pathway enzyme, is highly expressed in several cancers, including prostate cancer (PCa). To date, the mechanistic, functional, and clinical significance of FDPS in cancer remains unexplored. We evaluated the FDPS expression and its cancer-associated phenotypes using in vitro and in vivo methods in PTEN-deficient and sufficient human and mouse PCa cells and tumors. Interestingly, FDPS overexpression synergizes with PTEN deficiency in PTEN conditionally knockout mice (P < 0.05) and expressed significantly higher in human (P < 0.001) PCa tissues, cell lines, and murine tumoroids compared to respective controls. In silico analysis revealed that FDPS is associated with increasing Gleason score, PTEN functionally deficient status, and poor survival of PCa. Ectopic overexpression of FDPS promotes oncogenic phenotypes such as colony formation (P < 0.01) and proliferation (P < 0.01) through activation of AKT and ERK signaling by prenylating Rho A, Rho G, and CDC42 small GTPases. Of interest, knockdown of FDPS in PCa cells exhibits decreased colony growth and proliferation (P < 0.001) by modulating AKT and ERK pathways. Further, genetic and pharmacological inhibition of PI3K but not AKT reduced FDPS expression. Pharmacological targeting of FDPS by zoledronic acid (ZOL), which is already in clinics, exhibit reduced growth and clonogenicity of human and murine PCa cells (P < 0.01) and 3D tumoroids (P < 0.02) by disrupting AKT and ERK signaling through direct interference of small GTPases protein prenylation. Thus, FDPS plays an oncogenic role in PTEN-deficient PCa through GTPase/AKT axis. Identifying mevalonate pathway proteins could serve as a therapeutic target in PTEN dysregulated tumors.
| S-EPMC6597298 | biostudies-literature
Project description:PTEN is a tumor suppressor frequently deleted in prostate cancer that may be a useful prognostic biomarker. However, the association of PTEN loss with lethal disease has not been tested in a large, predominantly surgically treated cohort.In the Health Professionals Follow-up Study and Physicians' Health Study, we followed 1044 incident prostate cancer cases diagnosed between 1986 and 2009 for cancer-specific and all-cause mortality. A genetically validated PTEN immunohistochemistry (IHC) assay was performed on tissue microarrays (TMAs). TMPRSS2:ERG status was previously assessed in a subset of cases by a genetically validated IHC assay for ERG. Cox proportional hazards models adjusting for age and body mass index at diagnosis, Gleason grade, and clinical or pathologic TNM stage were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association with lethal disease. All statistical tests were two-sided.On average, men were followed 11.7 years, during which there were 81 lethal events. Sixteen percent of cases had complete PTEN loss in all TMA cores and 9% had heterogeneous PTEN loss across cores. After adjustment for clinical-pathologic variables, complete PTEN loss was associated with lethal progression (HR = 1.8, 95% CI = 1.2 to 2.9). The association of PTEN loss (complete or heterogeneous) with lethal progression was only among men with ERG-negative (HR = 3.1, 95% CI = 1.7 to 5.7) but not ERG-positive (HR = 1.2, 95% CI = 0.7 to 2.2) tumors.PTEN loss is independently associated with increased risk of lethal progression, particularly in the ERG fusion-negative subgroup. These validated and inexpensive IHC assays may be useful for risk stratification in prostate cancer.
| S-EPMC4862436 | biostudies-other
Project description:NKX3.1 is the most commonly deleted gene in prostate cancer and a gatekeeper suppressor. NKX3.1 is a growth suppressor, mediator of apoptosis, inducer of antioxidants, and enhancer of DNA repair. PTEN is a ubiquitous tumor suppressor that is often decreased in prostate cancer during tumor progression. Steady-state turnover of NKX3.1 is mediated by DYRK1B phosphorylation at NKX3.1 serine 185 that leads to polyubiquitination and proteasomal degradation. In this study, we show PTEN is an NKX3.1 phosphatase that protects NKX3.1 from degradation. PTEN specifically opposed phosphorylation at NKX3.1(S185) and prolonged NKX3.1 half-life. PTEN and NKX3.1 interacted primarily in the nucleus as loss of PTEN nuclear localization abrogated its ability to bind to and protect NKX3.1 from degradation. The effect of PTEN on NKX3.1 was mediated via rapid enzyme-substrate interaction. An effect of PTEN on Nkx3.1 gene transcription was seen in vitro, but not in vivo. In gene-targeted mice, Nkx3.1 expression significantly diminished shortly after loss of Pten expression in the prostate. Nkx3.1 loss primarily increased prostate epithelial cell proliferation in vivo. In these mice, Nkx3.1 mRNA was not affected by Pten expression. Thus, the prostate cancer suppressors PTEN and NKX3.1 interact and loss of PTEN is responsible, at least in part, for progressive loss of NKX3.1 that occurs during tumor progression. SIGNIFICANCE: PTEN functions as a phosphatase of NKX3.1, a gatekeeper suppressor of prostate cancer.
| S-EPMC6753942 | biostudies-literature
Project description:Loss of PTEN is a common genomic aberration in castration-resistant prostate cancer (CRPC) and is frequently concurrent with ERG rearrangements, causing resistance to next-generation hormonal treatment (NGHT) including abiraterone. The relationship between PTEN loss and docetaxel sensitivity remains uncertain.To study the antitumor activity of docetaxel in metastatic CRPC in relation to PTEN and ERG aberrations.Single-centre, retrospective analysis of PTEN loss and ERG expression using a previously described immunohistochemistry (IHC) binary classification system. Patients received docetaxel between January 1, 2006 and July 31, 2016.Response correlations were analyzed using Pearson's ?2 tests and independent-sample t tests. Overall (OS) and progression-free survival (PFS) were analyzed using univariate and multivariate (MVA) Cox regression and Kaplan-Meier methods.Overall, 215 patients were eligible. Established metastatic CRPC prognostic factors were well balanced between PTEN loss (39%) and normal patients (61%). PTEN loss was associated with shorter median OS (25.4 vs 34.7 mo; hazard ratio [HR] 1.66, 95% confidence interval [CI] 1.18-2.13; p = 0.001). There were no differences in median PFS (8.0 vs 9.1 mo; univariate HR 1.20, 95% CI 0.86-1.68; p = 0.28) and PSA response (53.4% vs 50.6%; p = 0.74). PTEN loss was an independent prognostics factor in MVA. ERG status was available for 100 patients. ERG positivity was not associated with OS or PFS. Limitations include the retrospective nature and the single-centre analysis.Our findings suggest that metastatic CRPC with PTEN loss might benefit more from docetaxel than from NGHT.In this study we found that metastatic prostate cancer with loss of the PTEN switch may benefit more from docetaxel than from abiraterone.
| S-EPMC5995869 | biostudies-other
Project description:E26 transformation-specific transcription factor ERG is aberrantly overexpressed in approximately 50% of all human prostate cancer due to TMPRSS2-ERG gene rearrangements. However, mice with prostate-specific transgenic expression of prostate cancer-associated ERG alone fail to develop prostate cancer, highlighting that ERG requires other lesions to drive prostate tumorigenesis. Forkhead box (FOXO) transcription factor FOXO1 is a tumor suppressor that is frequently inactivated in human prostate cancer. Here, we demonstrate that FOXO1, but not other FOXO proteins (FOXO3 and FOXO4), binds and inhibits the transcriptional activity of prostate cancer-associated ERG independently of FOXO1 transcriptional activity. Knockdown of endogenous FOXO1 increased invasion of TMPRSS2-ERG fusion-positive VCaP cells, an effect completely abolished by ERG knockdown. Patient specimen analysis demonstrated that FOXO1 and ERG protein expression inversely correlated in a subset of human prostate cancer. Although human ERG transgene expression or homozygous deletion of Foxo1 alone in the mouse prostate failed to promote tumorigenesis, concomitant ERG transgene expression and Foxo1 deletion resulted in upregulation of ERG target genes, increased cell proliferation, and formation of high-grade prostatic intraepithelial neoplasia. Overall, we provide biochemical and genetic evidence that aberrantly activated ERG cooperates with FOXO1 deficiency to promote prostate tumorigenesis and cell invasion. Our findings enhance understanding of prostate cancer etiology and suggest that the FOXO1-ERG signaling axis can be a potential target for treatment of prostate cancer. Cancer Res; 77(23); 6524-37. ©2017 AACR.
| S-EPMC5712249 | biostudies-literature
Project description:Understanding new therapeutic paradigms for both castrate-sensitive and more aggressive castrate-resistant prostate cancer is essential to improve clinical outcomes. As a critically important cellular process, autophagy promotes stress tolerance by recycling intracellular components to sustain metabolism important for tumor survival. To assess the importance of autophagy in prostate cancer, we generated a new autochthonous genetically engineered mouse model (GEMM) with inducible prostate-specific deficiency in the Pten tumor suppressor and autophagy-related-7 (Atg7) genes. Atg7 deficiency produced an autophagy-deficient phenotype and delayed Pten-deficient prostate tumor progression in both castrate-naïve and castrate-resistant cancers. Atg7-deficient tumors display evidence of endoplasmic reticulum (ER) stress, suggesting that autophagy may promote prostate tumorigenesis through management of protein homeostasis. Taken together, these data support the importance of autophagy for both castrate-naïve and castrate-resistant growth in a newly developed GEMM, suggesting a new paradigm and model to study approaches to inhibit autophagy in combination with known and new therapies for advanced prostate cancer.
| S-EPMC4762425 | biostudies-literature
Project description:Among frequent events in prostate cancer are loss of the tumor-suppressor phosphatase and tensin homologue (PTEN) and overexpression of prostate-specific G-protein-coupled receptor (PSGR), but the potential tumorigenic synergy between these lesions is unknown. Here, we report a new mouse model (PSGR-Pten(?/?)) combining prostate-specific loss of Pten with probasin promoter-driven PSGR overexpression. By 12 months PSGR-Pten(?/?) mice developed invasive prostate tumors featuring Akt activation and extensive inflammatory cell infiltration. PSGR-Pten(?/?) tumors exhibited E-cadherin loss and increased stromal androgen receptor (AR) expression. PSGR overexpression increased LNCaP proliferation, whereas PSGR short hairpin RNA knockdown inhibited proliferation and migration. In conclusion, we demonstrate that PSGR overexpression synergizes with loss of PTEN to accelerate prostate cancer development, and present a novel bigenic mouse model that mimics the human condition, where both PSGR overexpression and loss of PTEN occur concordantly in the majority of advanced prostate cancers, yielding an environment more relevant to studying human prostate cancer.
| S-EPMC4683109 | biostudies-literature
Project description:Both the PI3K ? Akt ? mTOR and mitogen-activated protein kinase (MAPK) signaling pathways are often deregulated in prostate tumors with poor prognosis. Here we describe a new genetically engineered mouse model of prostate cancer in which PI3K-Akt-mTOR signaling is activated by inducible disruption of PTEN, and extracellular signal-regulated kinase 1/2 (ERK1/2) MAPK signaling is activated by inducible expression of a BRAF(V600E) oncogene. These tissue-specific compound mutant mice develop lethal prostate tumors that are inherently resistant to castration. These tumors bypass cellular senescence and disseminate to lymph nodes, bone marrow, and lungs where they form overt metastases in approximately 30% of the cases. Activation of PI3K ? Akt ? mTOR and MAPK signaling pathways in these prostate tumors cooperate to upregulate c-Myc. Accordingly, therapeutic treatments with rapamycin and PD0325901 to target these pathways, respectively, attenuate c-Myc levels and reduce tumor and metastatic burden. Together, our findings suggest a generalized therapeutic approach to target c-Myc activation in prostate cancer by combinatorial targeting of the PI3K ? Akt ? mTOR and ERK1/2 MAPK signaling pathways.
| S-EPMC3445712 | biostudies-literature
Project description:The associations of ERG overexpression with clinical behavior and molecular pathways of prostate cancer are incompletely known. We assessed the association of ERG expression with AR, PTEN, SPINK1, Ki-67, and EZH2 expression levels, deletion, and mutations of chromosomal region 3p14 and TP53, and clinicopathologic variables.The material consisted of 326 prostatectomies, 166 needle biopsies from men treated primarily with endocrine therapy, 177 transurethral resections of castration-resistant prostate cancers (CRPC), and 114 CRPC metastases obtained from 32 men. Immunohistochemistry, FISH, and sequencing was used for the measurements.ERG expression was found in about 45% of all patient cohorts. In a multivariate analysis, ERG expression showed independent value of favorable prognosis (P = 0.019). ERG positivity was significantly associated with loss of PTEN expression in prostatectomy (P = 0.0348), and locally recurrent CRPCs (P = 0.0042). Loss of PTEN expression was associated (P = 0.0085) with shorter progression-free survival in ERG-positive, but not in negative cases. When metastases in each subject were compared, consistent ERG, PTEN, and AR expression as well as TP53 mutations were found in a majority of subjects.A similar frequency of ERG positivity from early to late stage of the disease suggests lack of selection of ERG expression during disease progression. The prognostic significance of PTEN loss solely in ERG-positive cases indicates interaction of these pathways. The finding of consistent genetic alterations in different metastases suggests that the major genetic alterations take place in the primary tumor.Interaction of PTEN and ERG pathways warrants further studies.
| S-EPMC4086660 | biostudies-literature
Project description:To elucidate the role of ETS gene fusions in castration-resistant prostate cancer (CRPC), we characterized the transcriptome of 54 CRPC tumor samples from men with locally advanced or metastatic disease. Trefoil factor 3 (TFF3) emerged as the most highly differentially regulated gene with respect to ERG rearrangement status and resistance to hormone ablation therapy. Conventional chromatin immunoprecipitation (ChIP)-polymerase chain reaction and ChIP followed by DNA sequencing (ChIP-seq) revealed direct binding of ERG to ETS binding sites in the TFF3 promoter in ERG-rearranged prostate cancer cell lines. These results were confirmed in ERG-rearranged hormone-naive prostate cancer (HNPC) and CRPC tissue samples. Functional studies demonstrated that ERG has an inhibitory effect on TFF3 expression in hormone-naive cancer but not in the castration-resistant state. In addition, we provide evidence suggesting an effect of androgen receptor signaling on ERG-regulated TFF3 expression. Furthermore, TFF3 overexpression enhances ERG-mediated cell invasion in CRPC prostate cancer cells. Taken together, our findings reveal a novel mechanism for enhanced tumor cell aggressiveness resulting from ERG rearrangement in the castration-resistant setting through TFF3 gene expression.
| S-EPMC3003138 | biostudies-literature