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Pten and prostate

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https://www.readbyqxmd.com/read/28726241/investigating-the-role-of-the-igf-axis-as-a-predictor-of-biochemical-recurrence-in-prostate-cancer-patients-post-surgery
#1
Kieran J Breen, Amanda O'Neill, Lisa Murphy, Yue Fan, Susie Boyce, Noel Fitzgerald, Emma Dorris, Lauren Brady, Stephen P Finn, Brian D Hayes, Ann Treacy, Ciara Barrett, Mardiana Abdul Aziz, Elaine W Kay, John M Fitzpatrick, R William G Watson
BACKGROUND: Between 20% and 35% of prostate cancer (PCa) patients who undergo treatment with curative intent (ie, surgery or radiation therapy) for localized disease will experience biochemical recurrence (BCR). Alterations in the insulin-like growth factor (IGF) axis and PTEN expression have been implicated in the development and progression of several human tumors including PCa. We examined the expression of the insulin receptor (INSR), IGF-1 receptor (IGF-1R), PTEN, and AKT in radical prostatectomy tissue of patients who developed BCR post-surgery...
July 20, 2017: Prostate
https://www.readbyqxmd.com/read/28714959/o-glcnacylation-modulates-bmi-1-protein-stability-and-potential-oncogenic-function-in-prostate-cancer
#2
Y Li, L Wang, J Liu, P Zhang, M An, C Han, Y Li, X Guan, K Zhang
The Polycomb group transcriptional repressor Bmi-1 often overexpressed and participated in stem cells self-renewal and tumorigenesis initiating of prostate cancer. In this progression, Bmi-1 protein was regulated by transcription and post-translational modifications (PTMs). Nobly, the underlying PTMs regulation of Bmi-1 is poorly known. Here we use co-immunoprecipitation show that in C4-2 cell line, Bmi-1 directly interacted with OGT which is the only known enzyme catalyzed the O-GlcNAcylation in human. Furthermore, we identified that Ser255 is the site for Bmi-1 O-GlcNAcylation, and O-GlcNAcylation promoted Bmi-1 protein stability and its oncogenic activity...
July 17, 2017: Oncogene
https://www.readbyqxmd.com/read/28699202/ductal-adenocarcinoma-of-the-prostate-clinical-and-biological-profiles
#3
Armelle Vinceneux, Franck Bruyère, Olivier Haillot, Thomas Charles, Alexandre de la Taille, Laurent Salomon, Yves Allory, Idir Ouzaid, Laurence Choudat, Morgan Rouprêt, Eva Comperat, Nadine Houede, Jean-Baptiste Beauval, Patrick Vourc'h, Gaëlle Fromont
BACKGROUND: Ductal adenocarcinoma (DAC) is a rare and aggressive subtype of prostate cancer (PCa). In the present study, we analyzed the clinical and biological characteristics of DAC, in comparison with high grade conventional acinar PCa. METHODS: Samples and data were retrospectively collected from seven institutions and centrally reviewed. Immunohistochemistry was performed on tissue microarrays to assess the expression of candidate proteins, based on the molecular classification of PCa, including ERG, PTEN, and SPINK1...
July 12, 2017: Prostate
https://www.readbyqxmd.com/read/28697730/dietary-supplementation-of-%C3%AE-linolenic-acid-induced-conversion-of-n-3-lcpufas-and-reduced-prostate-cancer-growth-in-a-mouse-model
#4
Jingjing Li, Zhennan Gu, Yong Pan, Shunhe Wang, Haiqin Chen, Hao Zhang, Wei Chen, Yong Q Chen
BACKGROUND: α-linolenic acid (ALA) is an n-3 polyunsaturated fatty acid (PUFA) and the substrate for long-chain n-3 PUFAs. The beneficial effects of ALA on chronic diseases are still in dispute, unlike those of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). METHODS: The primary objective of this investigation was to evaluate the efficiency of ALA uptake from a vegetable oil source and its subsequent conversion to n-3 long-chain PUFAs (LCPUFAs) in the tissues of growing mice, and to investigate its protective role in a prostate cancer animal model...
July 11, 2017: Lipids in Health and Disease
https://www.readbyqxmd.com/read/28684411/the-path-of-most-resistance-transdifferentiation-underlies-exceptional-nonresponses-to-androgen-receptor-pathway-inhibition-in-prostate-cancer
#5
Seema Sinha, Peter S Nelson
In this issue of Cancer Discovery, Zou and colleagues describe a mechanism involving cellular transdifferentiation that promotes exceptional resistance to antiandrogen therapy in prostate cancer. A background of coinactivation of Trp53 and Pten increased the frequency of the transdifferentiated neuroendocrine phenotype. These findings have implications for developing approaches to repress cellular plasticity and overcome treatment resistance. Cancer Discov; 7(7); 673-4. ©2017 AACRSee related article by Zou et al...
July 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28679531/transcriptional-regulation-of-nkx3-1-in-prostate-luminal-stem-cell-specification-and-cancer-initiation-via-its-3-genomic-region
#6
Qing Xie, Zhu A Wang
Nkx3.1, a transcription factor expressed in the prostate epithelium, is crucial for maintaining prostate cell fate and suppressing tumor initiation. Nkx3.1 is ubiquitously expressed in luminal cells of hormonally-intact prostate, but upon androgen deprivation, exclusively labels a type of luminal stem cells named castration-resistant Nkx3.1-expressing cells (CARNs). During prostate cancer initiation, Nkx3.1 expression is frequently lost in both humans and mouse models. Therefore, investigating how Nkx3.1 expression is regulated in vivo is important for understanding the mechanisms of prostate stem cell specification and cancer initiation...
July 5, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28662290/resveratrol-and-pterostilbene-as-a-microrna-mediated-chemopreventive-and-therapeutic-strategy-in-prostate-cancer
#7
REVIEW
Avinash Kumar, Agnes M Rimando, Anait S Levenson
Growing evidence indicates that deregulation of the epigenetic machinery comprising the microRNA (miRNA) network is a critical factor in the progression of various diseases, including cancer. Concurrently, dietary phytochemicals are being intensively studied for their miRNA-mediated health-beneficial properties, such as anti-inflammatory, cardioprotective, antioxidative, and anticancer properties. Available experimental data have suggested that dietary polyphenols may be effective miRNA-modulating chemopreventive and therapeutic agents...
June 29, 2017: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/28658205/mtorc1-dependent-amd1-regulation-sustains-polyamine-metabolism-in-prostate-cancer
#8
Amaia Zabala-Letona, Amaia Arruabarrena-Aristorena, Natalia Martín-Martín, Sonia Fernandez-Ruiz, James D Sutherland, Michelle Clasquin, Julen Tomas-Cortazar, Jose Jimenez, Ines Torres, Phong Quang, Pilar Ximenez-Embun, Ruzica Bago, Aitziber Ugalde-Olano, Ana Loizaga-Iriarte, Isabel Lacasa-Viscasillas, Miguel Unda, Verónica Torrano, Diana Cabrera, Sebastiaan M van Liempd, Ylenia Cendon, Elena Castro, Stuart Murray, Ajinkya Revandkar, Andrea Alimonti, Yinan Zhang, Amelia Barnett, Gina Lein, David Pirman, Ana R Cortazar, Leire Arreal, Ludmila Prudkin, Ianire Astobiza, Lorea Valcarcel-Jimenez, Patricia Zuñiga-García, Itziar Fernandez-Dominguez, Marco Piva, Alfredo Caro-Maldonado, Pilar Sánchez-Mosquera, Mireia Castillo-Martín, Violeta Serra, Naiara Beraza, Antonio Gentilella, George Thomas, Mikel Azkargorta, Felix Elortza, Rosa Farràs, David Olmos, Alejo Efeyan, Juan Anguita, Javier Muñoz, Juan M Falcón-Pérez, Rosa Barrio, Teresa Macarulla, Jose M Mato, Maria L Martinez-Chantar, Carlos Cordon-Cardo, Ana M Aransay, Kevin Marks, José Baselga, Josep Tabernero, Paolo Nuciforo, Brendan D Manning, Katya Marjon, Arkaitz Carracedo
Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation. Here we show that mechanistic target of rapamycin complex 1 (mTORC1) regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. By using integrative metabolomics in a mouse model and human biopsies of prostate cancer, we identify alterations in tumours affecting the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability...
July 6, 2017: Nature
https://www.readbyqxmd.com/read/28657117/low-grade-intraductal-carcinoma-of-the-prostate-an-idea-whose-time-has-not-yet-come
#9
Murali Varma
Shah et al describe a prostatic intraductal proliferation morphologically intermediate between high-grade PIN (HGPIN) and intraductal carcinoma (IDCP) for which they use the term "atypical intraductal proliferation (AIP).(1) They compared the clinicopathological and immunohistochemical characteristics (ERG and PTEN expression) of AIP and IDCP in consecutive prostate biopsies and concluded based on this and previous findings(2) that AIP represents lower-grade morphological spectrum of IDCP associated with an intermediate risk of associated prostate cancer compared to HGPIN and IDCP...
June 28, 2017: Histopathology
https://www.readbyqxmd.com/read/28645941/a-first-time-in-human-study-of-gsk2636771-a-phosphoinositide-3-kinase-beta-selective-inhibitor-in-patients-with-advanced-solid-tumors
#10
Joaquin Mateo, Gopinath Ganji, Charlotte Lemech, Howard A Burris, Sae-Won Han, Karen E Swales, Shaun Decordova, Maurice P DeYoung, Deborah A Smith, Shanker Kalyana-Sundaram, Jiuhua Wu, Monica Motwani, Rakesh Kumar, Jerry M Tolson, Sun Young Rha, Hyun Cheol Chung, Joseph Paul Eder, Sunil Sharma, Yung-Jue Bang, Jeffrey R Infante, Li Yan, Johann S de Bono, Hendrik-Tobias Arkenau
The phosphoinositide 3 kinase (PI3K)/protein kinase B (AKT) pathway is commonly activated in several tumor types. Selective targeting of p110β could result in successful pathway inhibition while avoiding the on and off target effects of pan-PI3K inhibitors. GSK2636771 is a potent, orally bioavailable, adenosine triphosphate-competitive, selective inhibitor of PI3Kβ.<br /><br />Experimental Design: <p>We evaluated the safety, pharmacokinetics, pharmacodynamics and antitumor activity of GSK2636771 to define the recommended Phase II dose (RP2D)...
June 23, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28631436/characterization-of-a-novel-p110%C3%AE-specific-inhibitor-bl140-that-overcomes-mdv3100-resistance-in-castration-resistant-prostate-cancer-cells
#11
Chenchen He, Shaofeng Duan, Liang Dong, Yifen Wang, Qingting Hu, Chunjing Liu, Marcus L Forrest, Jeffrey M Holzbeierlein, Suxia Han, Benyi Li
BACKGROUND: Our previous studies demonstrated that the class IA PI3K/p110β is critical in castration-resistant progression of prostate cancer (CRPC) and that targeting prostate cancer with nanomicelle-loaded p110β-specific inhibitor TGX221 blocked xenograft tumor growth in nude mice, confirming the feasibility of p110β-targeted therapy for CRPCs. To improve TGX221's aqueous solubility, in this study, we characterized four recently synthesized TGX221 analogs. METHODS: TGX221 analog efficacy were examined in multiple prostate cancer cell lines with the SRB cell growth assay, Western blot assay for AKT phosphorylation and cell cycle protein levels...
June 20, 2017: Prostate
https://www.readbyqxmd.com/read/28623072/commentary-on-integrative-clinical-genomics-of-advanced-prostate-cancer-robinson-d-van-allen-em-wu-ym-schultz-n-lonigro-rj-mosquera-jm-montgomery-b-taplin-me-pritchard-cc-attard-g-beltran-h-abida-w-bradley-rk-vinson-j-cao-x-vats-p-kunju-lp-hussain-m-feng-fy
#12
Stephen J Freedland, William J Aronson
Toward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%-60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF...
June 13, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/28618431/tumour-heterogeneity-poses-a-significant-challenge-to-cancer-biomarker-research
#13
Karolina Cyll, Elin Ersvær, Ljiljana Vlatkovic, Manohar Pradhan, Wanja Kildal, Marte Avranden Kjær, Andreas Kleppe, Tarjei S Hveem, Birgitte Carlsen, Silje Gill, Sven Löffeler, Erik Skaaheim Haug, Håkon Wæhre, Prasanna Sooriakumaran, Håvard E Danielsen
BACKGROUND: The high degree of genomic diversity in cancer represents a challenge for identifying objective prognostic markers. We aimed to examine the extent of tumour heterogeneity and its effect on the evaluation of a selected prognostic marker using prostate cancer as a model. METHODS: We assessed Gleason Score (GS), DNA ploidy status and phosphatase and tensin homologue (PTEN) expression in radical prostatectomy specimens (RP) from 304 patients followed for a median of 10 years (interquartile range 6-12)...
July 25, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28618395/erg-overexpression-plus-slc45a3-prostein-and-pten-expression-loss-strong-association-of-the-triple-hit-phenotype-with-an-aggressive-pathway-of-prostate-cancer-progression
#14
Silvia Hernández-Llodrà, Nuria Juanpere, Silvia de Muga, Marta Lorenzo, Joan Gil, Alba Font-Tello, Laia Agell, Raquel Albero-González, Laura Segalés, José Merino, Laia Serrano, Lluís Fumadó, Lluís Cecchini, Josep Lloreta Trull
TMPRSS2 and SLC45A3 rearrangements may coexist in the same tumor. ERG rearrangements and PTEN loss are concomitant events in prostate cancer (PrCa), and can cooperate in progression. We have reported that mRNA expression of TMPRSS2-ERG and SLC45A3-ERG rearrangements plus PTEN loss define an aggressive tumor subset. The aim of this study has been to validate these results by immunohistochemistry in a large cohort of tumors. ERG, SLC45A3 and PTEN immunostaining and their association with pathological features and PSA progression-free survival were analyzed in 220 PrCa (PSMAR-Biobank, Barcelona, Spain)...
May 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/28614300/pten-counteracts-fbxl2-to-promote-ip3r3-and-ca-2-mediated-apoptosis-limiting-tumour-growth
#15
Shafi Kuchay, Carlotta Giorgi, Daniele Simoneschi, Julia Pagan, Sonia Missiroli, Anita Saraf, Laurence Florens, Michael P Washburn, Ana Collazo-Lorduy, Mireia Castillo-Martin, Carlos Cordon-Cardo, Said M Sebti, Paolo Pinton, Michele Pagano
In response to environmental cues that promote IP3 (inositol 1,4,5-trisphosphate) generation, IP3 receptors (IP3Rs) located on the endoplasmic reticulum allow the 'quasisynaptical' feeding of calcium to the mitochondria to promote oxidative phosphorylation. However, persistent Ca(2+) release results in mitochondrial Ca(2+) overload and consequent apoptosis. Among the three mammalian IP3Rs, IP3R3 appears to be the major player in Ca(2+)-dependent apoptosis. Here we show that the F-box protein FBXL2 (the receptor subunit of one of 69 human SCF (SKP1, CUL1, F-box protein) ubiquitin ligase complexes) binds IP3R3 and targets it for ubiquitin-, p97- and proteasome-mediated degradation to limit Ca(2+) influx into mitochondria...
June 22, 2017: Nature
https://www.readbyqxmd.com/read/28614298/erf-mutations-reveal-a-balance-of-ets-factors-controlling-prostate-oncogenesis
#16
Rohit Bose, Wouter R Karthaus, Joshua Armenia, Wassim Abida, Phillip J Iaquinta, Zeda Zhang, John Wongvipat, Elizabeth V Wasmuth, Neel Shah, Patrick S Sullivan, Michael G Doran, Ping Wang, Anna Patruno, Yilin Zhao, Deyou Zheng, Nikolaus Schultz, Charles L Sawyers
Half of all prostate cancers are caused by the TMPRSS2-ERG gene-fusion, which enables androgens to drive expression of the normally silent E26 transformation-specific (ETS) transcription factor ERG in prostate cells. Recent genomic landscape studies of such cancers have reported recurrent point mutations and focal deletions of another ETS member, the ETS2 repressor factor ERF. Here we show these ERF mutations cause decreased protein stability and mostly occur in tumours without ERG upregulation. ERF loss recapitulates the morphological and phenotypic features of ERG gain in normal mouse prostate cells, including expansion of the androgen receptor transcriptional repertoire, and ERF has tumour suppressor activity in the same genetic background of Pten loss that yields oncogenic activity by ERG...
June 29, 2017: Nature
https://www.readbyqxmd.com/read/28603917/a-rare-castration-resistant-progenitor-cell-population-is-highly-enriched-in-pten-null-prostate-tumors
#17
Lucila Sackmann Sala, Florence Boutillon, Giulia Menara, Andréa De Goyon-Pélard, Mylène Leprévost, Julie Codzamanian, Natalie Lister, Jan Pencik, Ashlee Clark, Nicolas Cagnard, Christine Bole-Feysot, Richard Moriggl, Gail P Risbridger, Renea A Taylor, Lukas Kenner, Jacques-Emmanuel Guidotti, Vincent Goffin
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 LSC(med) according to their FACS profile (Lin(-) /Sca-1(+) /CD49f(med) ). Here we investigated the prevalence and castration-resistance of LSC(med) in various mouse models of prostate tumorigenesis (Pb-PRL, Pten(pc-/-) , Hi-Myc mice)...
June 12, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28600675/a-novel-capillary-nano-immunoassay-for-assessing-androgen-receptor-splice-variant-7-in-plasma-correlation-with-cd133-antigen-expression-in-circulating-tumor-cells-a-pilot-study-in-prostate-cancer-patients
#18
J L García, R Lozano, I Misiewicz-Krzeminska, J Fernández-Mateos, P Krzeminski, S Alfonso, R A Marcos, R García, F Gómez-Veiga, Á Virseda, M Herrero, D Olmos, J J Cruz-Hernández
PURPOSE: Androgen receptor (AR) splice variant 7 (AR-V7) has been related with both a higher risk of prostate cancer (PC) progression and differential responsiveness to hormonal agents versus chemotherapy. The objective of this study was to investigate the feasibility of a novel capillary nano-immunoassay in assessing AR-V7 in plasma from PC patients. METHODS: Patients with either localized or advanced PC were included in the study. Assessment of AR-V7 in plasma was performed through a capillary nano-immunoassay platform...
June 9, 2017: Clinical & Translational Oncology
https://www.readbyqxmd.com/read/28599295/inhibition-of-the-pi3k-akt-mtor-pathway-activates-autophagy-and-compensatory-ras-raf-mek-erk-signalling-in-prostate-cancer
#19
Dominika E Butler, Christopher Marlein, Hannah F Walker, Fiona M Frame, Vincent M Mann, Matthew S Simms, Barry R Davies, Anne T Collins, Norman J Maitland
The PI3K/AKT/mTOR pathway is frequently activated in advanced prostate cancer, due to loss of the tumour suppressor PTEN, and is an important axis for drug development. We have assessed the molecular and functional consequences of pathway blockade by inhibiting AKT and mTOR kinases either in combination or as individual drug treatments. In established prostate cancer cell lines, a decrease in cell viability and in phospho-biomarker expression was observed. Although apoptosis was not induced, a G1 growth arrest was observed in PTEN null LNCaP cells, but not in BPH1 or PC3 cells...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28599287/gene-polymorphisms-in-the-pi3k-akt-mtor-signaling-pathway-contribute-to-prostate-cancer-susceptibility-in-chinese-men
#20
Ting Liu, Abulajiang Gulinaer, Xiaoli Shi, Feng Wang, Hengqing An, Wenli Cui, Qiaoxin Li
In this hospital-based case-control study of 413 prostate cancer (PCa) cases and 807 cancer-free controls, we investigated the role of functional single nucleotide polymorphisms (SNPs) of pivotal genes in the PI3K/AKT/mTOR pathway. We genotyped 17 SNPs in mTOR, Raptor, AKT1, AKT2, PTEN, and K-ras and found that 4 were associated with PCa susceptibility. Among the variants, the homozygote variant CC genotype of mTOR rs17036508 C>T were associated with higher PCa risk than the wild TT genotypes (adjusted OR = 3...
May 22, 2017: Oncotarget
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