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‣ Comparative biomarker expression and RNA integrity in biospecimens derived from radical retropubic and robot-assisted laparoscopic prostatectomies

Ricciardelli, C.; Bianco-Miotto, T.; Jindal, S.; Dodd, T.; Cohen, P.; Marshall, V.; Sutherland, P.; Samaratunga, H.; Kench, J.; Dong, Y.; Wang, H.; Clements, J.; Risbridger, G.; Sutherland, R.; Tilley, W.; Horsfall, D.
Fonte: Amer Assoc Cancer Research Publicador: Amer Assoc Cancer Research
Tipo: Artigo de Revista Científica
Publicado em //2010 Português
Relevância na Pesquisa
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BACKGROUND: Knowledge of preanalytic conditions that biospecimens are subjected to is critically important because novel surgical procedures, tissue sampling, handling, and storage might affect biomarker expression or invalidate tissue samples as analytes for some technologies. METHODS: We investigated differences in RNA quality, gene expression by quantitative real-time PCR, and immunoreactive protein expression of selected prostate cancer biomarkers between tissues from retropubic radical prostatectomy (RRP) and robot-assisted laparoscopic prostatectomy (RALP). Sections of tissue microarray of 23 RALP and 22 RRP samples were stained with antibodies to androgen receptor (AR) and prostate-specific antigen (PSA) as intersite controls, and 14 other candidate biomarkers of research interest to three laboratories within the Australian Prostate Cancer BioResource tissue banking network. Quantitative real-time PCR was done for AR, PSA (KLK3), KLK2, KLK4, and HIF1A on RNA extracted from five RALP and five RRP frozen tissue cores. RESULTS: No histologic differences were observed between RALP and RRP tissue. Biomarker staining grouped these samples into those with increased (PSA, CK8/18, CKHMW, KLK4), decreased (KLK2, KLK14), or no change in expression (AR...

‣ Evidence for efficacy of new Hsp90 inhibitors revealed by ex vivo culture of human prostate tumors

Centenera, M.; Gillis, J.; Hanson, A.; Jindal, S.; Taylor, R.; Risbridger, G.; Sutherland, P.; Scher, H.; Raj, G.; Knudsen, K.; Yeadon, T.; Tilley, W.; Butler, L.
Fonte: Amer Assoc Cancer Research Publicador: Amer Assoc Cancer Research
Tipo: Artigo de Revista Científica
Publicado em //2012 Português
Relevância na Pesquisa
110.82641%
PURPOSE: Targeting Hsp90 has significant potential as a treatment for prostate cancer, but prototypical agents such as 17-allylamino-17 demethoxygeldanamycin (17-AAG) have been ineffective in clinical trials. Recently, a phase I study aimed at defining a biologically active dose reported the first response to an Hsp90 inhibitor in a patient with prostate cancer, which supports the development of new generation compounds for this disease. EXPERIMENTAL DESIGN: The biological actions of two new synthetic Hsp90 inhibitors, NVP-AUY922 and NVP-HSP990, were evaluated in the prostate cancer cell lines PC-3, LNCaP, and VCaP and in an ex vivo culture model of human prostate cancer. RESULTS: In cell lines, both NVP-AUY922 and NVP-HSP990 showed greater potency than 17-AAG with regard to modulation of Hsp90 client proteins, inhibition of proliferation, and induction of apoptotic cell death. In prostate tumors obtained from radical prostatectomy that were cultured ex vivo, treatment with 500 nmol/L of NVP-AUY922, NVP-HSP990, or 17-AAG caused equivalent target modulation, determined by the pharmacodynamic marker Hsp70, but only NVP-AUY922 and NVP-HSP990 showed antiproliferative and proapoptotic activity. CONCLUSIONS: This study provides some of the first evidence that new generation Hsp90 inhibitors are capable of achieving biologic responses in human prostate tumors...

‣ A gene signature identified using a mouse model of androgen receptor-dependent prostate cancer predicts biochemical relapse in human disease

Thompson, V.; Day, T.; Bianco-Miotto, T.; Selth, L.; Han, G.; Thomas, M.; Buchanan, G.; Scher, H.; Nelson, C.; Greenberg, N.; Butler, L.; Tilley, W.
Fonte: Wiley-liss Publicador: Wiley-liss
Tipo: Artigo de Revista Científica
Publicado em //2012 Português
Relevância na Pesquisa
89.96741%
Mutations in the androgen receptor (AR) have been detected in experimental and clinical prostate tumors. Mice with enforced prostate-specific expression of one such receptor variant, AR-E231G, invariably develop prostatic intraepithelial neoplasia by 12 weeks and metastatic prostate cancer by 52 weeks. The aim of this study was to identify genes with altered expression in the prostates of AR-E231G mice at an early stage of disease that may act as drivers of AR-mediated tumorigenesis. The gene expression profile of AR-E231G prostate tissue from 12-week-old mice was compared to an equivalent profile from mice expressing the AR-T857A receptor variant (analogous to the AR-T877A variant in LNCaP cells), which do not develop prostate tumors. One hundred and thirty-two genes were differentially expressed in AR-E231G prostates. Classification of these genes revealed enrichment for cellular pathways known to be involved in prostate cancer, including cell cycle and lipid metabolism. Suppression of two genes upregulated in the AR-E231G model, ADM and CITED1, increased cell death and reduced proliferation of human prostate cancer cells. Many genes differentially expressed in AR-E231G prostates are also deregulated in human tumors. Three of these genes...

‣ Circulating microRNAs predict biochemical recurrence in prostate cancer patients

Selth, L.; Townley, S.; Bert, A.; Stricker, P.; Sutherland, P.; Horvath, L.; Goodall, G.; Butler, L.; Tilley, W.
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
Relevância na Pesquisa
89.73225%
BACKGROUND: Circulating microRNAs (miRNAs) are emerging as promising biomarkers for prostate cancer. Here, we investigated the potential of these molecules to assist in prognosis and treatment decision-making. METHODS: MicroRNAs in the serum of patients who had experienced rapid biochemical recurrence (BCR) (n=8) or no recurrence (n=8) following radical prostatectomy (RP) were profiled using high-throughput qRT-PCR. Recurrence-associated miRNAs were subsequently quantitated by qRT-PCR in a validation cohort comprised of 70 patients with Gleason 7 cancers treated by RP, 31 of whom had undergone disease progression following surgery. The expression of recurrence-associated miRNAs was also examined in tumour tissue cohorts. RESULTS: Three miRNAs - miR-141, miR-146b-3p and miR-194 - were elevated in patients who subsequently experienced BCR in the screening study. MiR-146b-3p and miR-194 were also associated with disease progression in the validation cohort, as determined by log-rank tests and Cox proportional hazards regression. Multivariate analysis revealed that miR-146b-3p possessed prognostic information beyond standard clinicopathological parameters. Analysis of tissue cohorts revealed that miR-194 was robustly expressed in the prostate...

‣ Global levels of specific histone modifications and an epigenetic gene signature predict prostate cancer progression and development

Bianco-Miotto, T.; Chiam, K.; Buchanan, G.; Jindal, S.; Day, T.; Thomas, M.; Pickering, M.; O'Loughlin, M.; Ryan, N.; Raymond, W.; Horvath, L.; Kench, J.; Stricker, P.; Marshall, V.; Sutherland, R.; Henshall, S.; Gerald, W.; Scher, H.; Risbridger, G.; Cle
Fonte: Amer Assoc Cancer Research Publicador: Amer Assoc Cancer Research
Tipo: Artigo de Revista Científica
Publicado em //2010 Português
Relevância na Pesquisa
99.938545%
BACKGROUND: Epigenetic alterations are common in prostate cancer, yet how these modifications contribute to carcinogenesis is poorly understood. We investigated whether specific histone modifications are prognostic for prostate cancer relapse, and whether the expression of epigenetic genes is altered in prostate tumorigenesis. METHODS: Global levels of histone H3 lysine-18 acetylation (H3K18Ac) and histone H3 lysine-4 dimethylation (H3K4diMe) were assessed immunohistochemically in a prostate cancer cohort of 279 cases. Epigenetic gene expression was investigated in silico by analysis of microarray data from 23 primary prostate cancers (8 with biochemical recurrence and 15 without) and 7 metastatic lesions. RESULTS: H3K18Ac and H3K4diMe are independent predictors of relapse-free survival, with high global levels associated with a 1.71-fold (P < 0.0001) and 1.80-fold (P = 0.006) increased risk of tumor recurrence, respectively. High levels of both histone modifications were associated with a 3-fold increased risk of relapse (P < 0.0001). Epigenetic gene expression profiling identified a candidate gene signature (DNMT3A, MBD4, MLL2, MLL3, NSD1, and SRCAP), which significantly discriminated nonmalignant from prostate tumor tissue (P = 0.0063) in an independent cohort. CONCLUSIONS: This study has established the importance of histone modifications in predicting prostate cancer relapse and has identified an epigenetic gene signature associated with prostate tumorigenesis. IMPACT: Our findings suggest that targeting the epigenetic enzymes specifically involved in a particular solid tumor may be a more effective approach. Moreover...

‣ Characterization of the prostate cancer susceptibility gene KLF6 in human and mouse prostate cancers

Chiam, K.; Ryan, N.; Ricciardelli, C.; Day, T.; Buchanan, G.; Ochnik, A.; Murti, K.; Selth, L.; Butler, L.; Tilley, W.; Bianco-Miotto, T.
Fonte: Wiley-Liss Publicador: Wiley-Liss
Tipo: Artigo de Revista Científica
Publicado em //2013 Português
Relevância na Pesquisa
69.96415%
BACKGROUND: Krüppel-like factor (KLF) 6 is a candidate tumor suppressor gene in prostate cancer, but the mechanisms contributing to its loss of expression are poorly understood. We characterized KLF6 expression and DNA methylation status during prostate tumorigenesis in humans and mice. METHODS: KLF6 expression was assessed in matched human non-malignant (NM) and tumor prostate tissues (n = 22) by quantitative real-time PCR (qPCR) and in three independent human prostate cancer cohorts bioinformatically. QPCR for KLF6 expression and methylation-sensitive PCR (MSP) were performed in human prostate LNCaP cancer cells after 5-aza-2'-deoxycytidine treatment. Klf6 protein levels and DNA promoter methylation were assessed in TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) tumors by immunohistochemistry and MSP, respectively. RESULTS: KLF6 splice variants expression was increased (P = 0.0015) in human prostate tumors compared to NM tissues. Overall, KLF6 was decreased in metastatic compared to primary prostate cancers and reduced expression in primary tumors was associated with a shorter time to relapse (P = 0.0028). Treatment with the demethylating agent 5-aza-2'-deoxycytidine resulted in up-regulation of KLF6 expression (two-fold; P = 0.002) and a decrease in DNA methylation of the KLF6 promoter in LNCaP cells. Klf6 protein levels significantly decreased with progression in the TRAMP model of prostate cancer (P < 0.05)...