Urogenital System
- SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes
- Zine‐Eddine Kherraf1,†,
- Marie Christou‐Kent1,†,
- Thomas Karaouzene1,
- Amir Amiri‐Yekta1,2,3,
- Guillaume Martinez1,
- Alexandra S Vargas1,
- Emeline Lambert1,
- Christelle Borel4,
- Béatrice Dorphin5,
- Isabelle Aknin‐Seifer6,
- Michael J Mitchell7,
- Catherine Metzler‐Guillemain7,
- Jessica Escoffier1,
- Serge Nef4,
- Mariane Grepillat1,
- Nicolas Thierry‐Mieg8,
- Véronique Satre1,9,
- Marc Bailly10,11,
- Florence Boitrelle10,11,
- Karin Pernet‐Gallay12,
- Sylviane Hennebicq1,13,
- Julien Fauré2,12,
- Serge P Bottari1,14,
- Charles Coutton1,9,
- Pierre F Ray (pray{at}chu-grenoble.fr)*,1,2,‡ and
- Christophe Arnoult1,‡
- 1Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France
- 2CHU de Grenoble, UF de Biochimie Génétique et Moléculaire, Grenoble, France
- 3Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
- 4Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 4, Switzerland
- 5Laboratoire d'Aide Médicale à la Procréation, Centre AMP 74, Contamine‐sur‐Arve, France
- 6Laboratoire de Biologie de la Reproduction, Hôpital Nord, Saint Etienne, France
- 7Aix Marseille Univ INSERM GMGF, Marseille, France
- 8Univ. Grenoble Alpes / CNRS, TIMC‐IMAG, Grenoble, France
- 9CHU de Grenoble, UF de Génétique Chromosomique, Grenoble, France
- 10Department of Reproductive Biology and Gynaecology, Poissy General Hospital, Poissy, France
- 11EA 7404 GIG, Université de Versailles Saint Quentin Montigny le Bretonneux, France
- 12Grenoble Neuroscience Institute, INSERM 1216, Grenoble, France
- 13CHU de Grenoble, UF de Biologie de la procréation, Grenoble, France
- 14CHU de Grenoble, UF de Radioanalyses, Grenoble, France
- ↵*Corresponding author. Tel: +33 4 76 76 55 73; E‐mail: pray{at}chu-grenoble.fr
SPINK2, a serine protease inhibitor, is believed to target the acrosin, the main sperm acrosomal protease. This study confirms SPINK2 in that role and finds it essential for spermiogenesis as SPINK2 deficiency induces a post meiotic block at the round spermatid stage leading to azoospermia in mice and men.
Synopsis
SPINK2, a serine protease inhibitor, is believed to target the acrosin, the main sperm acrosomal protease. This study confirms SPINK2 in that role and finds it essential for spermiogenesis as SPINK2 deficiency induces a post meiotic block at the round spermatid stage leading to azoospermia in mice and men.
In round spermatids, SPINK2 is necessary to inactivate the acrosin during its transit through the endoplasmic reticulum and the Golgi apparatus.
In the absence of SPINK2, acrosin can auto‐activate, disorganize the Golgi apparatus, prevent the production of the acrosome and induce a block at the round spermatid stage.
A reduced amount of SPINK2 in heterozygotes is also deleterious, inducing a milder phenotype of oligozoospermia and/or teratozoospermia without a systematic infertility.
- Received December 13, 2016.
- Revision received April 14, 2017.
- Accepted April 26, 2017.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Deletion of F4L (ribonucleotide reductase) in vaccinia virus produces a selective oncolytic virus and promotes anti‐tumor immunity with superior safety in bladder cancer models
- Kyle G Potts1,2,3,
- Chad R Irwin2,3,4,
- Nicole A Favis2,3,4,
- Desmond B Pink1,3,
- Krista M Vincent1,3,5,
- John D Lewis1,3,
- Ronald B Moore1,3,6,
- Mary M Hitt1,2,3,† and
- David H Evans (devans{at}ualberta.ca)*,2,3,4,†
- 1Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- 2Li Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- 3Cancer Research Institute of Northern Alberta (CRINA), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- 4Department of Medical Microbiology & Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- 5Department of Anatomy & Cell Biology, Faculty of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
- 6Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- ↵*Corresponding author. Tel: +1 780 492‐7997; E‐mail: devans{at}ualberta.ca
↵† These authors contributed equally to this work
Vaccinia virus (VACV) mutated to render it incapable of synthesizing deoxynucleoside triphosphates (dNTPs) is a safe, highly selective, and potentially superior oncolytic agent in animal models for bladder cancer.
Synopsis
Vaccinia virus (VACV) mutated to render it incapable of synthesizing deoxynucleoside triphosphates (dNTPs) is a safe, highly selective, and potentially superior oncolytic agent in animal models for bladder cancer.
F4L‐deleted VACVs are highly attenuated in normal tissues and selectively replicate in, and kill bladder cancer cells that express elevated RRM2 levels.
F4L‐deleted VACVs replicate selectively in immune‐competent rat AY‐27 and xenografted human RT112‐luc orthotopic bladder cancer models, causing significant tumor regression or complete ablation with no toxicity.
Rats cured of AY‐27 tumors by VACV treatment developed long‐lasting anti‐tumor immunity.
F4L‐deleted VACVs replicate in primary human bladder cancer explants and BCG‐resistant cell lines.
EMBO Mol Med (2017) 9: 638–654
- Received November 4, 2016.
- Revision received February 10, 2017.
- Accepted February 15, 2017.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Ethics of stem cell‐derived gametes made in a dish: fertility for everyone?
A timely and thoughtful discussion of the ethical challenges and societal impacts presented by the recent reports demonstrating the successful in vitro generation of functional gametes from somatic and pluripotent stem cells.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- PPARG is central to the initiation and propagation of human angiomyolipoma, suggesting its potential as a therapeutic target
- Oren Pleniceanu1,2,3,4,
- Racheli Shukrun1,2,4,
- Dorit Omer1,2,
- Einav Vax1,2,4,
- Itamar Kanter5,
- Klaudyna Dziedzic1,2,4,
- Naomi Pode‐Shakked1,2,4,†,
- Michal Mark‐Daniei1,2,
- Sara Pri‐Chen1,2,
- Yehudit Gnatek1,2,
- Hadas Alfandary4,6,
- Nira Varda‐Bloom3,
- Dekel D Bar‐Lev1,2,
- Naomi Bollag7,
- Rachel Shtainfeld7,
- Leah Armon7,
- Achia Urbach7,
- Tomer Kalisky5,
- Arnon Nagler3,4,†,
- Orit Harari‐Steinberg1,2,
- Jack L Arbiser8,9 and
- Benjamin Dekel (benjamin.dekel{at}gmail.com) (binyamin.dekel{at}sheba.health.gov.il)*,1,2,4
- 1Pediatric Stem Cell Research Institute, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel
- 2Division of Pediatric Nephrology, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel
- 3Division of Hematology and Cord Blood Bank, Sheba Medical Center, Ramat Gan, Israel
- 4Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- 5Faculty of Engineering, Institute of Nanotechnology, Bar‐Ilan University, Ramat Gan, Israel
- 6Institute of Nephrology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
- 7The Mina and Everard Goodman Faculty of Life Sciences, Bar‐Ilan University, Ramat Gan, Israel
- 8Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA
- 9Winship Cancer Institute, Atlanta Veterans Administration Hospital, Atlanta, GA, USA
- ↵*Corresponding author. Tel: +972 3 5302445; Fax: +972 3 5303637; E‐mail: benjamin.dekel{at}gmail.com or binyamin.dekel{at}sheba.health.gov.il
Angiomyolipoma (AML) research is hampered by the lack of an animal model. In a novel in vivo human AML model, PPARG inhibition is identified as a potential therapy and the AML cell of origin as a resident MSC/pericyte skewed toward adipogenic differentiation.
Synopsis
Angiomyolipoma (AML) research is hampered by the lack of an animal model. In a novel in vivo human AML model, PPARG inhibition is identified as a potential therapy and the AML cell of origin as a resident MSC/pericyte skewed toward adipogenic differentiation.
An AML xenograft (Xn) model, exhibiting the classic histology, immunophenotype, and gene expression pattern of human AML, was established by injection of human AML cells in mice.
AML Xn propagation in vivo is accompanied by robust activation of the PPARG pathway, and human AML tumors strongly express PPARG.
PPARG is expressed across all tumor compartments, indicating that rather than accompanying adipocytic differentiation, PPARG activation drives AML growth, and with the presence of fat in the tumor being its by‐product.
PPARG antagonism, via small molecules and shRNA, results in strong growth inhibition of AML, as well as abrogation of tumor initiation in mice.
Human AML cells exhibit striking similarity to human MSCs, in terms of gene expression, surface marker expression, and potential.
EMBO Mol Med (2017) 9: 508–530
- Received November 29, 2015.
- Revision received January 19, 2017.
- Accepted January 26, 2017.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- VEGFA activates an epigenetic pathway upregulating ovarian cancer‐initiating cells
- Kibeom Jang1,2,
- Minsoon Kim1,2,
- Candace A Gilbert1,
- Fiona Simpkins1,3,7,
- Tan A Ince1,4,5 and
- Joyce M Slingerland (jslingerland{at}med.miami.edu)*,1,2,6
- 1Braman Family Breast Cancer Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
- 2Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA
- 3Department of Obstetrics & Gynecology, University of Miami Miller School of Medicine, Miami, FL, USA
- 4Department of Pathology, University of Miami Miller School of Medicine, Miami, FL, USA
- 5Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- 6Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
- 7Department of Obstetrics & Gynecology, University of Pennsylvania, Philadelphia, PA, USA
- ↵*Corresponding author. Tel: +1 305 243 7265; Fax: +1 305 243 6170; E‐mail: jslingerland{at}med.miami.edu
VEGFA is not only a key mediator of angiogenesis during tumor progression, but can also act to expand the population of ovarian cancer‐initiating cells with stem‐like properties.
Synopsis
VEGFA is not only a key mediator of angiogenesis during tumor progression, but can also act to expand the population of ovarian cancer‐initiating cells with stem‐like properties.
VEGFA increases sphere formation and ALDH1 activity of ovarian cancer cells in vitro and stimulates ovarian tumor‐initiating cells in vivo.
VEGFA rapidly activates VEGFR2 and Src to upregulate DNMT3 expression.
DNMT3A plays a pro‐oncogenic role to methylate miR‐128‐2 leading to Bmi1 and OVCA stem‐like cell upregulation.
High VEGFA and decreased miR‐128‐2 associate with poor ovarian cancer outcome.
EMBO Mol Med (2017) 9: 304–318
- Received July 19, 2016.
- Revision received December 16, 2016.
- Accepted December 19, 2016.
- © 2017 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Clusterin knockdown sensitizes prostate cancer cells to taxane by modulating mitosis
- Nader Al Nakouzi1,
- Chris Kedong Wang1,
- Eliana Beraldi1,
- Wolfgang Jager1,
- Susan Ettinger1,
- Ladan Fazli1,
- Lucia Nappi1,
- Jennifer Bishop1,
- Fan Zhang1,
- Anne Chauchereau2,3,
- Yohann Loriot2,3 and
- Martin Gleave*,1
- 1The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
- 2Department of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, University of Paris‐Sud, Villejuif, France
- 3INSERM U981, Villejuif, France
- ↵*Corresponding author. Tel: +1 604 875 4818; Fax: +1 604 875 5654; E‐mail: m.gleave{at}ubc.ca
CLU silencing sensitizes prostate cancer cells to taxane by inducing a constitutive activation of Cdc25C leading to a delay in exit from mitosis. In response, cells up‐regulate protective mechanisms through Wee1 kinase.
Synopsis
CLU silencing sensitizes prostate cancer cells to taxane by inducing a constitutive activation of Cdc25C leading to a delay in exit from mitosis. In response, cells up‐regulate protective mechanisms through Wee1 kinase.
CLU expression and Cdc25C expression are negatively correlated in prostate cancer cell lines, mice xenografts, and human biopsies.
CLU silencing induces accumulation of Cdc25C‐T48 phosphorylation.
Constitutive activation of Cdc25C by CLU silencing is compensated by Wee1 up‐regulation.
CLU silencing sensitizes PC3 cells to cabazitaxel, and inhibition of Wee1 improves synergistic responses to combination of taxanes and CLU inhibitors.
EMBO Mol Med (2016) 8: 761–778
- Received November 13, 2015.
- Revision received April 14, 2016.
- Accepted April 18, 2016.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- IGSF10 mutations dysregulate gonadotropin‐releasing hormone neuronal migration resulting in delayed puberty
- Sasha R Howard1,†,
- Leonardo Guasti1,†,
- Gerard Ruiz‐Babot1,
- Alessandra Mancini1,
- Alessia David2,
- Helen L Storr1,
- Lousie A Metherell1,
- Michael JE Sternberg2,
- Claudia P Cabrera3,4,
- Helen R Warren4,5,
- Michael R Barnes3,4,
- Richard Quinton6,
- Nicolas de Roux7,8,9,
- Jacques Young10,11,12,13,
- Anne Guiochon‐Mantel10,11,12,
- Karoliina Wehkalampi14,
- Valentina André15,
- Yoav Gothilf16,
- Anna Cariboni15,17 and
- Leo Dunkel*,1
- 1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- 2Centre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, Imperial College London, London, UK
- 3Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- 4NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK
- 5Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK
- 6Institute of Genetic Medicine University of Newcastle‐upon‐Tyne, Newcastle‐upon‐Tyne, UK
- 7Unité Mixte de Recherche 1141, Institut National de la Santé et de la Recherche Médicale, Paris, France
- 8Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France
- 9Laboratoire de Biochimie, Assistance Publique‐Hôpitaux de Paris, Hôpital Robert Debré, Paris, France
- 10Univ Paris‐Sud, Le Kremlin Bicêtre, France
- 11INSERM UMR‐1185, Le Kremlin Bicêtre, France
- 12Assistance Publique‐Hôpitaux de Paris, Bicêtre Hospital, Le Kremlin‐Bicêtre, France
- 13Department of Reproductive Endocrinology, Bicêtre Hospital, Le Kremlin‐Bicêtre, France
- 14Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- 15Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy
- 16Department of Neurobiology, The George S. Wise Faculty of Life Sciences and Sagol School of Neuroscience, Tel‐Aviv University, Tel Aviv, Israel
- 17Institute of Ophthalmology, University College London (UCL), London, UK
- ↵*Corresponding author. Tel: +44 207 882 6235; Fax: +44 207 882 6197; E‐mail: l.dunkel{at}qmul.ac.uk
↵† These authors contributed equally to this work
Self‐limited delayed puberty (DP) has strong familial inheritance, but the underlying genetic determinants are unknown. IGSF10 deficiency is found to affect embryonic GnRH neuronal migration and results in DP in humans.
Synopsis
Self‐limited delayed puberty (DP) has strong familial inheritance, but the underlying genetic determinants are unknown. IGSF10 deficiency is found to affect embryonic GnRH neuronal migration and results in DP in humans.
Pathogenic mutations in IGSF10 are found in patients with self‐limited delayed puberty.
IGSF10 is a gene of previously unclear function with no known human mutations.
IGSF10 is expressed within the nasal mesenchyme during fetal development, in a pattern similar to known chemokines that direct migrational GnRH neurons to the hypothalamus.
Knockdown of IGSF10 led to a reduced migration of GnRH neurons in vitro and in a transgenic zebrafish model.
IGSF10 loss‐of‐function mutations were also identified in patients with hypothalamic amenorrhea, suggesting an overlapping genetic and mechanistic basis between different types of functional hypogonadotropic hypogonadism, including DP and hypothalamic amenorrhea.
EMBO Mol Med (2016) 8: 626–642
- Received January 26, 2016.
- Revision received March 1, 2016.
- Accepted March 14, 2016.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Characterization and quantification of proteins secreted by single human embryos prior to implantation
- Maurizio Poli1,2,3,†,
- Alessandro Ori4,†,
- Tim Child1,2,
- Souraya Jaroudi3,
- Katharina Spath1,3,
- Martin Beck4 and
- Dagan Wells*,1,3
- 1Nuffield Department of Obstetrics and Gynaecology, Institute of Reproductive Sciences University of Oxford, Oxford, UK
- 2Oxford Fertility Unit, Institute of Reproductive Sciences, Oxford, UK
- 3Reprogenetics UK, Institute of Reproductive Sciences, Oxford, UK
- 4European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany
- ↵*Corresponding author. Tel: +44 1865 782800; E‐mail: dagan.wells{at}obs-gyn.ox.ac.uk
↵† These authors contributed equally to this work
To maximise in vitro fertilization success rate, the embryo prioritized for transfer must be the most capable within the cohort of embryos generated by the patient. The blastocentesis procedure described here could be a way to get there.
Synopsis
To maximise in vitro fertilization success rate, the embryo prioritized for transfer must be the most capable within the cohort of embryos generated by the patient. The blastocentesis procedure described here could be a way to get there.
Blastocentesis is a novel micromanipulation technique used to collect a 4 nL sample of blastocoelic fluid from living human embryos.
A catalogue of 182 proteins secreted by the human blastocyst and validated by microarray gene expression analysis of whole human embryo is provided.
Targeted mass spectrometry approach enables the measurement of nine proteins of interest from single human blastocoels.
Blastocentesis has no long‐term impact on embryo overall architecture, suggesting its potential application in a clinical setting.
EMBO Mol Med (2015) 7: 1465–1479
- Received April 15, 2015.
- Revision received September 3, 2015.
- Accepted September 15, 2015.
- © 2015 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression
- Chunbo He1,2,
- Dagan Mao1,3,
- Guohua Hua1,2,
- Xiangmin Lv1,
- Xingcheng Chen4,
- Peter C Angeletti5,
- Jixin Dong4,
- Steven W Remmenga1,4,
- Kerry J Rodabaugh1,
- Jin Zhou1,6,
- Paul F Lambert7,
- Peixin Yang8,
- John S Davis1,4,9 and
- Cheng Wang*,1,4
- 1Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA
- 2College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
- 3College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
- 4Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
- 5Nebraska Center for Virology, School of Biological Sciences, University of Nebraska‐Lincoln, Lincoln, NE, USA
- 6Department of Obstetrics and Gynecology, Urumqi General Hospital of Lanzhou Military Region, Urumqi, China
- 7Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- 8Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
- 9Omaha Veterans Affairs Medical Center, Omaha, NE, USA
- ↵*Corresponding author. Tel: +1 402 559 8665; Fax: +1 402 559 1159; E‐mail: chengwang{at}unmc.edu
The dysregulated Hippo/YAP signaling pathway participates in an autocrine loop that promotes cervical carcinogenesis via interactions with the ERBB signaling pathway. HPV early proteins facilitate cervical tumorigenesis by stabilizing YAP oncoproteins.
Synopsis
The dysregulated Hippo/YAP signaling pathway participates in an autocrine loop that promotes cervical carcinogenesis via interactions with the ERBB signaling pathway. HPV early proteins facilitate cervical tumorigenesis by stabilizing YAP oncoproteins.
The main components of the Hippo/YAP pathway are dysregulated in cervical cancer leading to overexpression and activation of the YAP oncoprotein.
Ectopic expression of wild‐type or constitutively active YAP induced transformation of cervical epithelial cells and enhanced growth and migration of cervical cancer cells.
The Hippo/YAP pathway interacts with the ERBB signaling pathway to form a positive feed‐forward loop to drive the development and progression of cervical cancer.
The HPV E6 protein stabilizes the YAP protein in cervical cancer cells to support the proliferative signaling loop.
Combined targeting of the Hippo and the ERBB signaling pathways may provide a new therapeutic strategy for prevention and treatment of cervical cancer.
EMBO Mol Med (2015) 7: 1426–1449
- Received December 19, 2014.
- Revision received August 18, 2015.
- Accepted August 20, 2015.
- © 2015 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Androgen receptor profiling predicts prostate cancer outcome
- Suzan Stelloo1,†,
- Ekaterina Nevedomskaya1,2,†,
- Henk G van der Poel3,
- Jeroen de Jong4,
- Geert JLH van Leenders5,
- Guido Jenster6,
- Lodewyk FA Wessels2,
- Andries M Bergman*,7 and
- Wilbert Zwart*,1
- 1Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- 2Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- 3Division of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- 4Division of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- 5Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam, The Netherlands
- 6Department of Urology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam, The Netherlands
- 7Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- ↵*
Corresponding author. Tel: +31 20 512 2101; E‐mail: a.bergman{at}nki.nl
Corresponding author. Tel: +31 20 512 2101; E‐mail: w.zwart{at}nki.nl
↵† These authors contributed equally to this study
Investigation of chromatin accessibility in prostate specimens identified potential driving transcription factors in prostate tumorigenesis, including androgen receptor (AR). AR ChIP‐seq unveiled distinct profiles that bear prognostic potential and can stratify patients on outcome.
Synopsis
Investigation of chromatin accessibility in prostate specimens identified potential driving transcription factors in prostate tumorigenesis, including androgen receptor (AR). AR ChIP‐seq unveiled distinct profiles that bear prognostic potential and can stratify patients on outcome.
Chromatin is more condensed in healthy prostate as opposed to prostate tumors.
Motif sequences for AR and its interactors are enriched at accessible chromatin sites.
AR chromatin binding sites differ between primary and progressive prostate cancer.
Genes with a proximal differentially bound AR chromatin site can stratify patients with prostate cancer on outcome.
The gene classifier can be used alone or in combination with the D'Amico classification to improve risk stratification for biochemical recurrence.
EMBO Mol Med (2015) 7: 1450–1464
- Received May 8, 2015.
- Revision received September 1, 2015.
- Accepted September 3, 2015.
- © 2015 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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