Complete loss of PTEN expression as a possible early prognostic marker for prostate cancer metastasis

Schmitz, Martine; Grignard, Gérard; Margue, Christiane; Dippel, Walter; Capesius, C.; Mossong, Joël; Nathan, Michel; Giacchi, Sandro; Scheiden, R; Kieffer, Nelly

doi:10.1002/ijc.22359

Cited by 109 publications

(97 citation statements)

References 46 publications

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“…In previous studies, PTEN was tested in PCa and hyperplastic prostate tissues, and it was observed to be mainly expressed in PCa tissues and in the cell nuclei of hyperplastic prostate tissues (28,29). The expression of PTEN in PCa was significantly higher than that in prostate hyperplasia, which indicated that increased PTEN expression levels may be associated with the incidence of PCa (30,31). In the present study, treatment with DPPT significantly promoted PTEN protein expression in DU-145 cells.…”

Section: Discussionsupporting

confidence: 56%

Anticancer effect of deoxypodophyllotoxin induces apoptosis of human prostate cancer cells

Zhou

et al. 2016

Oncology Letters

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Abstract. Deoxypodophyllotoxin (DPPT) is extracted and separated from citrus-related plants, including Podophyllum (P.) peltatum, P. pleianthum, P. emodi (also called P. hexandrum) and Diphylleia grayi. DPPT has significant antitumor and antiviral activity. However, due to its strong toxicity and side effects, its use is limited in practical applications. The in vitro antitumor efficacy of DPPT on human prostate cancer (PCa) cells remains to be determined. The present study investigated the anticancer effect of DPPT on human PCa cells and its potential mechanism. The data revealed that DPPT markedly reduced cell proliferation and activated the caspase-3 expression level by an increase in apoptotic cell death in DU-145 cells. In addition, treatment with DPPT markedly downregulated the levels of phosphorylated Akt and activated the p53/B-cell lymphoma 2 associated X protein (Bax)/phosphatase and tensin homolog (PTEN) signaling pathway in DU-145 cells, suggesting that caspase-mediated pathways were involved in DPPT-induced apoptosis. The present study suggested the role of DPPT as a novel chemotherapeutic drug for human PCa, which may function through the Akt/p53/Bax/PTEN signaling pathway.

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Section: Discussionsupporting

confidence: 56%

Anticancer effect of deoxypodophyllotoxin induces apoptosis of human prostate cancer cells

Zhou

et al. 2016

Oncology Letters

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“…Finally, although not replicated in the Swedish cohort, we found attenuation of the potent tumour-suppressor phosphatase and tensin homologue, PTEN, in TMPRSS2 -ERG fusion-positive tumours. Loss of PTEN expression has been strongly associated with prostate cancer progression (Koksal et al, 2004;Bertram et al, 2006;Yoshimoto et al, 2006a;Schmitz et al, 2007) and has recently been implicated as cooperating with TMPRSS2 -ERG fusion in high-grade prostatic intraepithelial neoplasia King et al, 2009). Loss of PTEN results in PI3K activation, which in turn can be targeted with emerging modalities inhibiting PI3K or PI3K and mTor such as SF1126 and BEZ235, respectively.…”

Section: Discussionmentioning

confidence: 99%

Prostate cancer genes associated with TMPRSS2–ERG gene fusion and prognostic of biochemical recurrence in multiple cohorts

et al. 2010

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BACKGROUND: Recent studies have indicated that prostate cancer patients with the TMPRSS2 -ERG gene fusion have a higher risk of recurrence. To identify markers associated with TMPRSS2 -ERG fusion and prognostic of biochemical recurrence, we analysed a cohort of 139 men with prostate cancer for 502 molecular markers. METHODS: RNA from radical prostatectomy tumour specimens was analysed using cDNA-mediated, annealing, selection, extension and ligation (DASL) to determine mRNAs associated with TMPRSS2 -ERG T1/E4 fusion and prognostic of biochemical recurrence. Differentially expressed mRNAs in T1/E4-positive tumours were determined using significance analysis of microarrays (false discovery rate (FDR) o5%). Univariate and multivariate Cox regression determined genes, gene signatures and clinical factors prognostic of recurrence (P-value o0.05, log -rank test). Analysis of two prostate microarray studies (GSE1065 and GSE8402) validated the findings. RESULTS: In the 139 patients from this study and from a 455-patient Swedish cohort, 15 genes in common were differentially regulated in T1/E4 fusion-positive tumours (FDR o0.05). The most significant mRNAs in both cohorts coded ERG. Nine genes were found prognostic of recurrence in this study and in a 596-patient Minnesota cohort. A molecular recurrence score was significant in prognosticating recurrence (P-value 0.000167) and remained significant in multivariate analysis of a mixed clinical model considering Gleason score and TMPRSS2 -ERG fusion status. CONCLUSIONS: TMPRSS2 -ERG T1/E4 fusion-positive tumours had differentially regulated mRNAs observed in multiple studies, the most significant one coded for ERG. Several mRNAs were consistently associated with biochemical recurrence and have potential clinical utility but will require further validation for successful translation.

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“…[29][30][31] PTEN deletions are found in approximately 40% of localized prostate cancers. 8,14,[31][32][33][34][35][36][37][38][39][40][41][42][43][44] In advanced disease, fluorescence in situ hybridization (FISH) has identified hemizygous (loss of one copy) and homozygous (loss of both copies) PTEN deletions, 31,39,43,45,46 with the incidence of PTEN deletion approaching 70-80% of castrate-resistant tumors. 33,40,42,43 It has been shown that hemizygous PTEN deletions are associated with earlier biochemical relapse.…”

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confidence: 99%

PTEN losses exhibit heterogeneity in multifocal prostatic adenocarcinoma and are associated with higher Gleason grade

et al. 2013

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Prostatic adenocarcinoma is an epithelial malignancy characterized by marked histological heterogeneity. It most often has a multifocal distribution within the gland, and different Gleason grades may be present within different foci. Data from our group and others have shown that the genomic deletion of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene and the disruption of the ETS gene family have a central role in prostate cancer and are likely to be associated with Gleason grade. In this study, prostate cancer samples were systematically analyzed to determine whether there was concordance between PTEN losses and TMPRSS2-ERG fusion rearrangements, within or between foci in multifocal disease, using well-annotated tissue microarrays (TMAs) consisting of 724 cores derived from 142 radical prostatectomy specimens. Three-color fluorescence in situ hybridization analysis of both the PTEN deletion and the TMPRSS2-ERG fusion was used to precisely map genetic heterogeneity, both within and between tumor foci represented on the TMA. PTEN deletion was observed in 56 of 134 (42%) patients (hemizygous ¼ 42 and homozygous ¼ 14). TMPRSS2-ERG fusion was observed in 63 of 139 (45%) patients. When analyzed by Gleason pattern for a given TMA core, PTEN deletions were significantly associated with Gleason grades 4 or 5 over grade 3 (Po0.001). Although TMPRSS2-ERG fusions showed a strong relationship with PTEN deletions (P ¼ 0.007), TMPRSS2-ERG fusions did not show correlation with Gleason grade. The pattern of genetic heterogeneity of PTEN deletion was more diverse than that observed for TMPRSS2-ERG fusions in multifocal disease. However, the marked interfocal discordance for both TMPRSS2-ERG fusions and PTEN deletions was consistent with the concept that multiple foci of prostate cancer arise independently within the same prostate, and that individual tumor foci can have distinct patterns of genetic rearrangements.

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Complete loss of PTEN expression as a possible early prognostic marker for prostate cancer metastasis

Cited by 109 publications

References 46 publications

Anticancer effect of deoxypodophyllotoxin induces apoptosis of human prostate cancer cells

Anticancer effect of deoxypodophyllotoxin induces apoptosis of human prostate cancer cells

Prostate cancer genes associated with TMPRSS2–ERG gene fusion and prognostic of biochemical recurrence in multiple cohorts

PTEN losses exhibit heterogeneity in multifocal prostatic adenocarcinoma and are associated with higher Gleason grade

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