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Pten and prostate

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https://www.readbyqxmd.com/read/28106991/discovery-of-a-phosphoinositide-3-kinase-pi3k-b-d-inhibitor-for-the-treatment-of-phosphatase-and-tensin-homolog-pten-deficient-tumors-building-pi3kb-potency-in-a-pi3kd-selective-template-by-targeting-non-conserved-asp856
#1
Stéphane Perreault, Jayaraman Chandrasekhar, Zhi-Hua Cui, Jerry B Evarts, Jia Hao, Joshua A Kaplan, Adam Kashishian, Kathleen S Keegan, Thomas Kenney, David J Koditek, Latesh Lad, Eve-Irene Lepist, Mary E McGrath, Leena Patel, Bart Phillips, Joseph Therrien, Jennifer Treiberg, Anella Yahiaoui, Gary Phillips
Phosphoinositide 3-kinase (PI3K) beta signaling is required to sustain cancer cell growth in which the tumor suppressor phosphatase and tensin homolog (PTEN) has been deactivated. This manuscript describes the discovery, optimization, and in vivo evaluation of a novel series of PI3Kbeta/delta inhibitors in which PI3Kbeta potency was built in a PI3Kdelta-selective template. This work led to the discovery of a highly selective PI3Kbeta/delta inhibitor displaying excellent pharmacokinetic profile and efficacy in a human PTEN-deficient LNCaP prostate carcinoma xenograft tumor model...
January 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28059767/rb1-and-trp53-cooperate-to-suppress-prostate-cancer-lineage-plasticity-metastasis-and-antiandrogen-resistance
#2
Sheng Yu Ku, Spencer Rosario, Yanqing Wang, Ping Mu, Mukund Seshadri, Zachary W Goodrich, Maxwell M Goodrich, David P Labbé, Eduardo Cortes Gomez, Jianmin Wang, Henry W Long, Bo Xu, Myles Brown, Massimo Loda, Charles L Sawyers, Leigh Ellis, David W Goodrich
Prostate cancer relapsing from antiandrogen therapies can exhibit variant histology with altered lineage marker expression, suggesting that lineage plasticity facilitates therapeutic resistance. The mechanisms underlying prostate cancer lineage plasticity are incompletely understood. Studying mouse models, we demonstrate that Rb1 loss facilitates lineage plasticity and metastasis of prostate adenocarcinoma initiated by Pten mutation. Additional loss of Trp53 causes resistance to antiandrogen therapy. Gene expression profiling indicates that mouse tumors resemble human prostate cancer neuroendocrine variants; both mouse and human tumors exhibit increased expression of epigenetic reprogramming factors such as Ezh2 and Sox2...
January 6, 2017: Science
https://www.readbyqxmd.com/read/28057891/prostate-cancer-pi3k-pten-and-prognosis
#3
REVIEW
Helen M Wise, Miguel A Hermida, Nicholas R Leslie
Loss of function of the PTEN tumour suppressor, resulting in dysregulated activation of the phosphoinositide 3-kinase (PI3K) signalling network, is recognized as one of the most common driving events in prostate cancer development. The observed mechanisms of PTEN loss are diverse, but both homozygous and heterozygous genomic deletions including PTEN are frequent, and often accompanied by loss of detectable protein as assessed by immunohistochemistry (IHC). The occurrence of PTEN loss is highest in aggressive metastatic disease and this has driven the development of PTEN as a prognostic biomarker, either alone or in combination with other factors, to distinguish indolent tumours from those likely to progress...
February 1, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/28009609/atypical-intraductal-cribriform-proliferations-of-the-prostate-exhibit-similar-molecular-and-clinicopathologic-characteristics-as-intraductal-carcinoma-of-the-prostate
#4
Richard A Hickman, Hui Yu, Jianhong Li, Max Kong, Rajal B Shah, Ming Zhou, Jonathan Melamed, Fang-Ming Deng
Atypical intraductal cribriform proliferations of the prostate (AIP) are loose cribriform proliferations of luminal cells that exhibit greater architectural complexity and/or nuclear atypia than high-grade prostatic intraepithelial neoplasia (HGPIN), but lack the diagnostic criteria for intraductal carcinoma (IDC). The significance of AIP has not been formally established. We compared the clinical, morphologic, and immunohistochemical characteristics of AIP with classic IDC in 310 radical prostatectomy specimens that were received over an 18-month period...
December 22, 2016: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/27995550/somatic-mutations-in-prostate-cancer-closer-to-personalized-medicine
#5
REVIEW
M J Alvarez-Cubero, L J Martinez-Gonzalez, I Robles-Fernandez, J Martinez-Herrera, G Garcia-Rodriguez, M Pascual-Geler, J M Cozar, J A Lorente
The molecular cause of prostate cancer (PCa) is still unclear; however, its progression involves androgen, PI3K/Akt, and PTEN signaling, as cycle and apoptotic pathways. Alterations in oncogenes and tumor suppressor genes as PIK3CA, BRAF, KRAS and TP53 are not very common. Recently, somatic mutations have been discovered in relation to cancer progression mainly in genes such as PIK3CA; however, little data has been described in PCa. Nowadays genetic tools allow us to investigate multiple details about the biological heterogeneity of PCa, to better understand the mechanisms of disease progression and treatment resistance...
December 19, 2016: Molecular Diagnosis & Therapy
https://www.readbyqxmd.com/read/27955654/depletion-of-sag-rbx2-e3-ubiquitin-ligase-suppresses-prostate-tumorigenesis-via-inactivation-of-the-pi3k-akt-mtor-axis
#6
Mingjia Tan, Jie Xu, Javed Siddiqui, Felix Feng, Yi Sun
BACKGROUND: SAG (Sensitive to Apoptosis Gene), also known as RBX2, ROC2 or RNF7, is a RING component of CRL (Cullin-RING ligase), required for its activity. Our recent study showed that SAG/RBX2 co-operated with Kras to promote lung tumorigenesis, but antagonized Kras to inhibit skin tumorigenesis, suggesting a tissue/context dependent function of Sag. However, it is totally unknown whether and how Sag would play in prostate tumorigenesis, triggered by Pten loss. METHODS: Sag and Pten double conditional knockout mice were generated and prostate specific deletion of Sag and Pten was achieved by PB4-Cre, and their effect on prostate tumorigenesis was evaluated by H&E staining...
December 12, 2016: Molecular Cancer
https://www.readbyqxmd.com/read/27941799/inhibition-of-notch-pathway-arrests-pten-deficient-advanced-prostate-cancer-by-triggering-p27-driven-cellular-senescence
#7
Ajinkya Revandkar, Maria Luna Perciato, Alberto Toso, Abdullah Alajati, Jingjing Chen, Hermeto Gerber, Mitko Dimitrov, Andrea Rinaldi, Nicolas Delaleu, Emiliano Pasquini, Rocco D'Antuono, Sandra Pinton, Marco Losa, Letizia Gnetti, Alberto Arribas, Patrick Fraering, Francesco Bertoni, Alain Nepveu, Andrea Alimonti
Activation of NOTCH signalling is associated with advanced prostate cancer and treatment resistance in prostate cancer patients. However, the mechanism that drives NOTCH activation in prostate cancer remains still elusive. Moreover, preclinical evidence of the therapeutic efficacy of NOTCH inhibitors in prostate cancer is lacking. Here, we provide evidence that PTEN loss in prostate tumours upregulates the expression of ADAM17, thereby activating NOTCH signalling. Using prostate conditional inactivation of both Pten and Notch1 along with preclinical trials carried out in Pten-null prostate conditional mouse models, we demonstrate that Pten-deficient prostate tumours are addicted to the NOTCH signalling...
December 12, 2016: Nature Communications
https://www.readbyqxmd.com/read/27941540/new-and-emerging-diagnostic-and-prognostic-immunohistochemical-biomarkers-in-prostate-pathology
#8
REVIEW
Giovanna A Giannico, Shanna A Arnold, Lan L Gellert, Omar Hameed
The diagnosis of minimal prostatic adenocarcinoma can be challenging on prostate needle biopsy, and immunohistochemistry may be used to support the diagnosis of cancer. The International Society of Urologic Pathology currently recommends the use of the basal cell markers high-molecular-weight cytokeraratin and p63, and α-methylacyl-coenzyme-A racemase. However, there are caveats associated with the interpretation of these markers, particularly with benign mimickers. Another issue is that of early detection of presence and progression of disease and prediction of recurrence after clinical intervention...
January 2017: Advances in Anatomic Pathology
https://www.readbyqxmd.com/read/27935821/stromal-hedgehog-signaling-maintains-smooth-muscle-and-hampers-micro-invasive-prostate-cancer
#9
Zhaohui Yang, Yu-Ching Peng, Anuradha Gopalan, Dong Gao, Yu Chen, Alexandra L Joyner
It is widely appreciated that reactive stroma or carcinoma-associated fibroblasts can influence epithelial tumor progression. In prostate cancer (PCa), the second most common male malignancy worldwide, the amount of reactive stroma is variable and has predictive value for tumor recurrence. By analyzing human PCa protein and RNA expression databases, we found smooth muscle cells (SMCs) are decreased in advanced tumors, whereas fibroblasts are maintained. In three mouse models of PCa, PB-MYC, ERG/PTEN and TRAMP, we found the composition of the stroma is distinct...
January 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/27916292/cancer-prognosis-defined-by-the-combined-analysis-of-8q-pten-and-erg
#10
Maria P Silva, João D Barros-Silva, Elin Ersvær, Wanja Kildal, Tarjei Sveinsgjerd Hveem, Manohar Pradhan, Joana Vieira, Manuel R Teixeira, Håvard E Danielsen
Overtreatment is a major concern in men diagnosed with prostate cancer. The aim of this study was to evaluate the combined prognostic role of three frequent molecular alterations in prostate cancer, namely relative 8q gain, ERG overexpression, and loss of PTEN expression, in a series of 136 patients with prostate cancer treated with prostatectomy and with a long follow-up. Fluorescent in situ hybridization was used to detect the relative copy number of 8q and immunohistochemistry was used for quantitative assessment of ERG and PTEN expression...
December 2016: Translational Oncology
https://www.readbyqxmd.com/read/27913052/evaluation-of-erg-and-pten-protein-expression-in-cribriform-architecture-prostate-carcinomas
#11
Michelle R Downes, Swati Satturwar, Dominique Trudel, Theo H van der Kwast
ERG and PTEN have been suggested as potential prognostic markers in prostatic adenocarcinoma. We assessed the relationship between ERG and PTEN protein expression in cribriform architecture prostatic carcinomas and adjacent acinar non-cribriform carcinoma and determined the interobserver variability in assessment of these markers. A contemporary cohort of radical prostatectomy cases (n=246) were reviewed and cribriform architecture carcinomas (intraductal carcinoma and cribriform Gleason 4 carcinomas) were identified and confirmed with triple cocktail immunostaining...
January 2017: Pathology, Research and Practice
https://www.readbyqxmd.com/read/27880722/deletion-of-8p-is-an-independent-prognostic-parameter-in-prostate-cancer
#12
Martina Kluth, Nina Nadine Amschler, Rami Galal, Christina Möller-Koop, Phillipp Barrow, Maria Christina Tsourlakis, Frank Jacobsen, Andrea Hinsch, Corinna Wittmer, Stefan Steurer, Till Krech, Franziska Büscheck, Till Sebastian Clauditz, Burkhard Beyer, Waldemar Wilczak, Markus Graefen, Hartwig Huland, Sarah Minner, Thorsten Schlomm, Guido Sauter, Ronald Simon
Deletion of chromosome 8p is the second most frequent genomic alteration in prostate cancer. To better understand its clinical significance, 8p deletion was analyzed by fluorescence in-situ hybridization on a prostate cancer tissue microarray. 8p deletion was found in 2,581 of 7,017 cancers (36.8%), and was linked to unfavorable tumor phenotype. 8p deletion increased from 29.5% in 4,456 pT2 and 47.8% in 1,598 pT3a to 53.0% in 931 pT3b-pT4 cancers (P < 0,0001). Deletions of 8p were detected in 25.5% of 1,653 Gleason ≤ 3 + 3, 36...
November 17, 2016: Oncotarget
https://www.readbyqxmd.com/read/27869166/skp2-loss-destabilizes-ezh2-by-promoting-traf6-mediated-ubiquitination-to-suppress-prostate-cancer
#13
W Lu, S Liu, B Li, Y Xie, M G Izban, B R Ballard, S A Sathyanarayana, S E Adunyah, R J Matusik, Z Chen
EZH2 is crucial for the progression of prostate cancer (PCa) and castration-resistant prostate cancer (CRPC) through upregulation and activation of progenitor genes, as well as androgen receptor (AR)-target genes. However, the mechanisms by which EZH2 is regulated in PCa and CRPC remain elusive. Here we report that EZH2 is post-transcriptionally regulated by SKP2 in vitro in cultured cells and in vivo in mouse models. We observed aberrant upregulation of Skp2, Ezh2 and histone H3 lysine 27 trimethylation (H3K27me3) in both Pten null mouse embryonic fibroblasts (MEFs) and Pten null mouse prostate tissues...
November 21, 2016: Oncogene
https://www.readbyqxmd.com/read/27863384/a-novel-highly-potent-trivalent-tgf-%C3%AE-receptor-trap-inhibits-early-stage-tumorigenesis-and-tumor-cell-invasion-in-murine-pten-deficient-prostate-glands
#14
Tai Qin, Lindsey Barron, Lu Xia, Haojie Huang, Maria M Villarreal, John Zwaagstra, Cathy Collins, Junhua Yang, Christian Zwieb, Ravindra Kodali, Cynthia S Hinck, Sun Kyung Kim, Robert L Reddick, Chang Shu, Maureen D O'Connor-McCourt, Andrew P Hinck, Lu-Zhe Sun
The effects of transforming growth factor beta (TGF-β) signaling on prostate tumorigenesis has been shown to be strongly dependent on the stage of development, with TGF-β functioning as a tumor suppressor in early stages of disease and as a promoter in later stages. To study in further detail the paradoxical tumor-suppressive and tumor-promoting roles of the TGF-β pathway, we investigated the effect of systemic treatment with a TGF-β inhibitor on early stages of prostate tumorigenesis. To ensure effective inhibition, we developed and employed a novel trivalent TGF-β receptor trap, RER, comprised of domains derived from the TGF-β type II and type III receptors...
November 14, 2016: Oncotarget
https://www.readbyqxmd.com/read/27852060/senp1-regulates-pten-stability-to-dictate-prostate-cancer-development
#15
Tasneem Bawa-Khalfe, Feng-Ming Yang, Joan Ritho, Hui-Kuan Lin, Jinke Cheng, Edward T H Yeh
SUMO protease SENP1 is elevated in multiple carcinomas including prostate cancer (PCa). SENP1 exhibits carcinogenic properties; it promotes androgen receptor-dependent and -independent cell proliferation, stabilizes HIF1α, increases VEGF, and supports angiogenesis. However, mice expressing an androgen-responsive promoter driven SENP1-transgene (SENP1-Tg) develop high-grade prostatic intraepithelial neoplasia, but not carcinoma. We now show that tumor suppressive PTEN signaling is induced in SENP1-Tg to enhance prostate epithelial cell apoptosis...
November 10, 2016: Oncotarget
https://www.readbyqxmd.com/read/27851748/chromosomal-instability-estimation-based-on-next-generation-sequencing-and-single-cell-genome-wide-copy-number-variation-analysis
#16
Stephanie B Greene, Angel E Dago, Laura J Leitz, Yipeng Wang, Jerry Lee, Shannon L Werner, Steven Gendreau, Premal Patel, Shidong Jia, Liangxuan Zhang, Eric K Tucker, Michael Malchiodi, Ryon P Graf, Ryan Dittamore, Dena Marrinucci, Mark Landers
Genomic instability is a hallmark of cancer often associated with poor patient outcome and resistance to targeted therapy. Assessment of genomic instability in bulk tumor or biopsy can be complicated due to sample availability, surrounding tissue contamination, or tumor heterogeneity. The Epic Sciences circulating tumor cell (CTC) platform utilizes a non-enrichment based approach for the detection and characterization of rare tumor cells in clinical blood samples. Genomic profiling of individual CTCs could provide a portrait of cancer heterogeneity, identify clonal and sub-clonal drivers, and monitor disease progression...
2016: PloS One
https://www.readbyqxmd.com/read/27807828/anxa7-gtpase-as-tumor-suppressor-mechanisms-and-therapeutic-opportunities
#17
Ximena Leighton, Ofer Eidelman, Catherine Jozwik, Harvey B Pollard, Meera Srivastava
Chromosomal abnormalities, including homozygous deletions and loss of heterozygosity at 10q, are commonly observed in most human tumors, including prostate, breast, and kidney cancers. The ANXA7-GTPase is a tumor suppressor, which is frequently inactivated by genomic alterations at 10q21. In the last few years, considerable amounts of data have accumulated describing inactivation of ANXA7-GTPase in a variety of human malignancies and demonstrating the tumor suppressor potential of ANXA7-GTPase. ANXA7-GTPase contains a calcium binding domain that classifies it as a member of the annexin family...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27807665/a-new-transgenic-mouse-model-for-conditional-overexpression-of-the-polycomb-group-protein-ezh2
#18
Martijn A J Koppens, Ellen Tanger, Karim Nacerddine, Bart Westerman, Ji-Ying Song, Maarten van Lohuizen
The Polycomb Group protein EZH2 is upregulated in most prostate cancers, and its overexpression is associated with poor prognosis. Most insights into the functional role of EZH2 in prostate cancer have been gained using cell lines and EZH2 inactivation studies. However, the question remains whether overexpression of EZH2 can initiate prostate tumourigenesis or drive tumour progression. Appropriate transgenic mouse models that are required to answer such questions are lacking. We developed one such transgenic mouse model for conditional overexpression of Ezh2...
November 2, 2016: Transgenic Research
https://www.readbyqxmd.com/read/27803051/up-regulation-of-mismatch-repair-genes-msh6-pms2-and-mlh1-parallels-development-of-genetic-instability-and-is-linked-to-tumor-aggressiveness-and-early-psa-recurrence-in-prostate-cancer
#19
Waldemar Wilczak, Semin Rashed, Claudia Hube-Magg, Martina Kluth, Ronald Simon, Franziska Büscheck, Till Sebastian Clauditz, Katharina Grupp, Sarah Minner, Maria Christina Tsourlakis, Christina Möller-Koop, Markus Graefen, Meike Adam, Alexander Haese, Corinna Wittmer, Guido Sauter, Jakob Robert Izbicki, Hartwig Huland, Thorsten Schlomm, Stefan Steurer, Till Krech, Patrick Lebok
DNA mismatch repair (MMR) is integral to the maintenance of genetic stability. We aimed to evaluate the clinical impact of MMR gene expression in prostate cancer. The MMR genes MSH6, MLH1 and PMS2 were analyzed by immunohistochemistry on a tissue microarray containing 11152 prostate cancer specimens. Results were compared with ETS-related gene status and deletions of PTEN, 3p13, 5q21 and 6q15. MSH6, MLH1 and PMS2 expression was detectable in 89.5%, 85.4% and 85.0% of cancers and was particularly strong in cancers with advanced pathological tumor stage (P < 0...
January 2017: Carcinogenesis
https://www.readbyqxmd.com/read/27754870/transgenic-expression-of-the-mitochondrial-chaperone-tnfr-associated-protein-1-trap1-accelerates-prostate-cancer-development
#20
Sofia Lisanti, David S Garlick, Kelly G Bryant, Michele Tavecchio, Gordon B Mills, Yiling Lu, Andrew V Kossenkov, Louise C Showe, Lucia R Languino, Dario C Altieri
Protein homeostasis, or proteostasis, is required for mitochondrial function, but its role in cancer is controversial. Here we show that transgenic mice expressing the mitochondrial chaperone TNFR-associated protein 1 (TRAP1) in the prostate develop epithelial hyperplasia and cellular atypia. When examined on a Pten(+/-) background, a common alteration in human prostate cancer, TRAP1 transgenic mice showed accelerated incidence of invasive prostatic adenocarcinoma, characterized by increased cell proliferation and reduced apoptosis, in situ Conversely, homozygous deletion of TRAP1 delays prostatic tumorigenesis in Pten(+/-) mice without affecting hyperplasia or prostatic intraepithelial neoplasia...
November 25, 2016: Journal of Biological Chemistry
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