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  • 1.
    Antoniou, Antonis C.
    et al.
    Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    Beesley, Jonathan
    Queensland Institute of Medical Research, Brisbane, Australia.
    McGuffog, Lesley
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    M. Sinilnikova, Olga
    Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, Lyon, France.
    Healey, Sue
    Queensland Institute Med Research, Brisbane, Qld, Australia.
    L. Neuhausen, Susan
    Beckman Research Institute City Hope, Department Populat Science, Duarte, CA USA.
    Chun Ding, Yuan
    Beckman Research Institute City Hope, Department Populat Science, Duarte, CA USA.
    R. Rebbeck, Timothy
    University Penn, Sch Med, Abramson Canc Centre, Philadelphia, PA 19104 USA.
    N. Weitzel, Jeffrey
    City Hope Natl Med Centre, Duarte, CA 91010 USA.
    T. Lynch, Henry
    Creighton University, Omaha, NE 68178 USA.
    Isaacs, Claudine
    A. Ganz, Patricia
    University Calif Los Angeles, Jonsson Comprehens Canc Centre, Los Angeles, CA 90024 USA.
    Tomlinson, Gail
    University Texas Hlth Science Centre San Antonio, San Antonio, TX 78229 USA.
    I. Olopade, Olufunmilayo
    University Chicago, Med Centre, Chicago, IL 60637 USA.
    J. Couch, Fergus
    Mayo Clin, Department Lab Med and Pathol, Rochester, MN USA.
    Wang, Xianshu
    Mayo Clin, Department Lab Med and Pathol, Rochester, MN USA.
    M. Lindor, Noralane
    Mayo Clin, Department Med Genet, Rochester, MN USA.
    S. Pankratz, Vernon
    Mayo Clin, Department Hlth Science Research, Rochester, MN USA.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Unit Genet Susceptibil Canc, Department Expt Oncol and Mol Med, Milan, Italy.
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Department Prevent and Predict Med, Milan, Italy.
    Peissel, Bernard
    Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Department Prevent and Predict Med, Milan, Italy.
    Zaffaroni, Daniela
    Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Department Prevent and Predict Med, Milan, Italy.
    Barile, Monica
    IEO, Div Canc Prevent and Genet, Milan, Italy.
    Viel, Alessandra
    IRCCS, CRO, Div Expt Oncol 1, Aviano, PN, Italy.
    Allavena, Anna
    University Turin, Department Genet Biol and Biochem, Turin, Italy.
    DallOlio, Valentina
    Cogentech, Consortium Genom Technology, Milan, Italy.
    Peterlongo, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Unit Genet Susceptibil Canc, Department Expt Oncol and Mol Med, Milan, Italy.
    I. Szabo, Csilla
    Mayo Clin, Coll Med, Department Lab Med and Pathol, Rochester, MN USA.
    Zikan, Michal
    Charles University Prague, Fac Med 1, Department Biochem and Expt Oncol, Prague, Czech Republic.
    Claes, Kathleen
    Ghent University Hospital, Centre Med Genet, B-9000 Ghent, Belgium.
    Poppe, Bruce
    Ghent University Hospital, Centre Med Genet, B-9000 Ghent, Belgium.
    Foretova, Lenka
    Masaryk Mem Canc Institute, Department Canc Epidemiol and Genet, Brno, Czech Republic.
    L. Mai, Phuong
    US Natl Canc Institute, Clin Genet Branch, Rockville, MD USA.
    H. Greene, Mark
    US Natl Canc Institute, Clin Genet Branch, Rockville, MD USA.
    Rennert, Gad
    Technion Israel Institute Technology, Carmel Med Centre, Haifa, Israel.
    Lejbkowicz, Flavio
    Technion Israel Institute Technology, Carmel Med Centre, Haifa, Israel.
    Glendon, Gord
    OCGN, Toronto, ON, Canada.
    Ozcelik, Hilmi
    Mt Sinai Hospital, Fred A Litwin Centre Canc Genet, Samuel Lunenfeld Research Institute, New York, NY 10029 USA.
    L. Andrulis, Irene
    OCGN, Toronto, ON, Canada.
    Thomassen, Mads
    Odense University Hospital, Department Clin Genet, DK-5000 Odense, Denmark.
    Gerdes, Anne-Marie
    Rigshosp, Department Clin Genet, Odense, Denmark.
    Sunde, Lone
    Aalborg Hospital, Department Clin Genet, Aalborg, Denmark.
    Cruger, Dorthe
    Vejle Hospital, Department Clin Genet, Velje, Denmark.
    Birk Jensen, Uffe
    Aarhus University Hospital, Department Clin Genet, DK-8000 Aarhus, Denmark.
    Caligo, Maria
    University Pisa, Div Surg Mol and Ultrastruct Pathol, Department Oncol, Pisa, Italy.
    Friedman, Eitan
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Kaufman, Bella
    Sheba Med Centre, Institute Oncol, Tel Hashomer, Israel.
    Laitman, Yael
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Milgrom, Roni
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Dubrovsky, Maya
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Cohen, Shimrit
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Borg, Ake
    Lund University, Department Oncol, Lund, Sweden.
    Jernstroem, Helena
    Lund University, Department Oncol, Lund, Sweden.
    Lindblom, Annika
    Karolinska Institute, Department Mol Med and Surg, Stockholm, Sweden.
    Rantala, Johanna
    Karolinska Institute, Department Mol Med and Surg, Stockholm, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Melin, Beatrice
    Umea University, Department Radiat Science, Umea, Sweden.
    Nathanson, Kate
    University Penn, Philadelphia, PA 19104 USA.
    Domchek, Susan
    University Penn, Philadelphia, PA 19104 USA.
    Jakubowska, Ania
    Pomeranian Med University, Int Hereditary Canc Centre, Department Genet and Pathol, Szczecin, Poland.
    Lubinski, Jan
    Pomeranian Med University, Int Hereditary Canc Centre, Department Genet and Pathol, Szczecin, Poland.
    Huzarski, Tomasz
    Pomeranian Med University, Int Hereditary Canc Centre, Department Genet and Pathol, Szczecin, Poland.
    Osorio, Ana
    Spanish Natl Canc Research Centre, Human Genet Grp, Human Canc Genet Programme, Madrid, Spain.
    Lasa, Adriana
    Hospital Santa Creu and Sant Pau, Genet Serv, Barcelona, Spain.
    Duran, Mercedes
    University Valladolid, Institute Biol and Mol Genet, IBGM UVA, Valladolid, Spain.
    Tejada, Maria-Isabel
    Cruces Hospital Barakaldo, Mol Genet Lab, Department Biochem, Bizkaia, Spain.
    Godino, Javier
    University Lozano Blesa, Hospital Clin, Oncol Serv, Zaragoza, Spain.
    Benitez, Javier
    Spanish Natl Canc Research Centre, Human Canc Genet Programme, Genotyping Unit, Madrid, Spain.
    Hamann, Ute
    Deutsch Krebsforschungszentrum, Mol Genet Breast Canc, D-6900 Heidelberg, Germany.
    Kriege, Mieke
    Daniel Denhoed Canc Centre, Erasmus MC, Department Med Oncol, Family Canc Clin, Rotterdam, Netherlands.
    Hoogerbrugge, Nicoline
    Radboud University Nijmegen, Nijmegen Med Centre, Hereditary Canc Clin, NL-6525 ED Nijmegen, Netherlands.
    B. van der Luijt, Rob
    University Med Centre Utrecht, Department Med Genet, Utrecht, Netherlands.
    J. van Asperen, Christi
    Leiden University, Med Centre, Department Clin Genet, Leiden, Netherlands.
    Devilee, Peter
    Leiden University, Department Human Genet, Med Centre, Department Pathol, NL-2300 RA Leiden, Netherlands.
    J. Meijers-Heijboer, E.
    Vrije University Amsterdam Med Centre, Department Clin Genet, Amsterdam, Netherlands.
    J. Blok, Marinus
    University Med Centre, Department Genet and Cell Biol, Maastricht, Netherlands.
    M. Aalfs, Cora
    University Amsterdam, Acad Med Centre, Department Clin Genet, NL-1105 AZ Amsterdam, Netherlands.
    Hogervorst, Frans
    Netherlands Canc Institute, Family Canc Clin, Amsterdam, Netherlands.
    Rookus, Matti
    Netherlands Canc Institute, Department Epidemiol, Amsterdam, Netherlands.
    Cook, Margaret
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    Oliver, Clare
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    Frost, Debra
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    Conroy, Don
    University Cambridge, Department Oncol, Cambridge, England.
    Gareth Evans, D.
    Cent Manchester University Hospital NHS Fdn Trust, Manchester Acad Hlth Science Centre, Manchester, Lancs, England.
    Lalloo, Fiona
    Cent Manchester University Hospital NHS Fdn Trust, Manchester Acad Hlth Science Centre, Manchester, Lancs, England.
    Pichert, Gabriella
    Guys and St Thomas NHS Fdn Trust, London, England.
    Davidson, Rosemarie
    Ferguson Smith Centre Clin Genet, Glasgow, Lanark, Scotland.
    Cole, Trevor
    Birmingham Womens Hospital Healthcare NHS Trust, W Midlands Reg Genet Serv, Birmingham, W Midlands, England.
    Cook, Jackie
    Sheffield Childrens Hospital, Sheffield Clin Genet Serv, Sheffield, S Yorkshire, England.
    Paterson, Joan
    Addenbrookes Hospital, Department Clin Genet, E Anglian Reg Genet Serv, Cambridge, England.
    Hodgson, Shirley
    University London, Department Clin Genet, St Georges Hospital, London, England.
    J. Morrison, Patrick
    Belfast City Hospital, Northern Ireland Reg Genet Centre, Belfast BT9 7AD, Antrim, North Ireland.
    E. Porteous, Mary
    Western Gen Hospital, SE Scotland Reg Genet Serv, Edinburgh EH4 2XU, Midlothian, Scotland.
    Walker, Lisa
    Churchill Hospital, Oxford Reg Genet Serv, Oxford OX3 7LJ, England.
    John Kennedy, M.
    St James Hospital, Canc Genet Program, Hope Directorate, Dublin, Ireland.
    Dorkins, Huw
    Kennedy Galton Centre, NW Thames Reg Genet Serv, Harrow, Middx, England.
    Peock, Susan
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    K. Godwin, Andrew
    Fox Chase Canc Centre, Department Med Oncol, Womens Canc Program, Philadelphia, PA 19111 USA.
    Stoppa-Lyonnet, Dominique
    University Paris 05, INSERM, U509, Serv Genet Oncol,Institute Curie, Paris, France.
    de Pauw, Antoine
    University Paris 05, INSERM, U509, Serv Genet Oncol,Institute Curie, Paris, France.
    Mazoyer, Sylvie
    University Lyon 1, CNRS, Centre Leon Berard, Equipe Labellisee LIGUE 2008,UMR5201, F-69365 Lyon, France.
    Bonadona, Valerie
    University Lyon 1, CNRS, UMR5558, F-69365 Lyon, France.
    Lasset, Christine
    University Lyon 1, CNRS, UMR5558, F-69365 Lyon, France.
    Dreyfus, Helene
    CHU Grenoble, Department Genet, F-38043 Grenoble, France.
    Leroux, Dominique
    CHU Grenoble, Department Genet, F-38043 Grenoble, France.
    Hardouin, Agnes
    Centre Francois Baclesse, F-14021 Caen, France.
    Berthet, Pascaline
    Centre Francois Baclesse, F-14021 Caen, France.
    Faivre, Laurence
    Centre Hospital University Dijon, Centre Genet, Dijon, France.
    Loustalot, Catherine
    Centre Lutte Canc Georges Francois Leclerc, Dijon, France.
    Noguchi, Tetsuro
    INSERM, Institute Paoli Calmettes, UMR599, Department Oncol Genet, F-13258 Marseille, France.
    Sobol, Hagay
    INSERM, Institute Paoli Calmettes, UMR599, Department Oncol Genet, F-13258 Marseille, France.
    Rouleau, Etienne
    Centre Rene Huguenin, INSERM, U735, St Cloud, France.
    Nogues, Catherine
    Frenay, Marc
    Centre Antoine Lacassagne, F-06054 Nice, France.
    Venat-Bouvet, Laurence
    Centre Hospital University Limoges, Department Oncol, Limoges, France.
    L. Hopper, John
    University Melbourne, Melbourne, Vic, Australia.
    B. Daly, Mary
    Fox Chase Canc Centre, Department Med Oncol, Womens Canc Program, Philadelphia, PA 19111 USA.
    B. Terry, Mary
    Columbia University, New York, NY USA.
    M. John, Esther
    Canc Prevent Institute Calif, Fremont, CA USA.
    S. Buys, Saundra
    University Utah, Hlth Science Centre, Huntsman Canc Institute, Salt Lake City, UT USA.
    Yassin, Yosuf
    Dana Farber Canc Institute, Boston, MA 02115 USA.
    Miron, Alexander
    Dana Farber Canc Institute, Boston, MA 02115 USA.
    Goldgar, David
    University Utah, Department Dermatol, Salt Lake City, UT USA.
    F. Singer, Christian
    Med University Vienna, Department Obstet and Gynecol, Vienna, Austria.
    Catharina Dressler, Anne
    Med University Vienna, Department Obstet and Gynecol, Vienna, Austria.
    Gschwantler-Kaulich, Daphne
    Med University Vienna, Department Obstet and Gynecol, Vienna, Austria.
    Pfeiler, Georg
    Med University Vienna, Department Obstet and Gynecol, Vienna, Austria.
    V. O. Hansen, Thomas
    University Copenhagen, Rigshosp, Department Clin Biochem, DK-2100 Copenhagen, Denmark.
    Jnson, Lars
    University Copenhagen, Rigshosp, Department Clin Biochem, DK-2100 Copenhagen, Denmark.
    A. Agnarsson, Bjarni
    University Hospital, Department Pathol, Reykjavik, Iceland.
    Kirchhoff, Tomas
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA.
    Offit, Kenneth
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA.
    Devlin, Vincent
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA.
    Dutra-Clarke, Ana
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA.
    Piedmonte, Marion
    Roswell Pk Canc Institute, GOG Stat and Data Centre, Buffalo, NY 14263 USA.
    C. Rodriguez, Gustavo
    NorthShore University Hlth Syst, Evanston NW Healthcare, Evanston, IL USA.
    Wakeley, Katie
    Tufts University, New England Med Centre, Boston, MA 02111 USA.
    F. Boggess, John
    University N Carolina, Chapel Hill, NC USA.
    Basil, Jack
    St Elizabeth Hospital, Edgewood, KY USA.
    E. Schwartz, Peter
    Yale University, Sch Med, New Haven, CT USA.
    V. Blank, Stephanie
    NYU, Sch Med, New York, NY USA.
    Ewart Toland, Amanda
    Ohio State University, Centre Comprehens Canc, Department Internal Med and Mol Virol, Div Human Canc Genet, Columbus, OH 43210 USA.
    Montagna, Marco
    IRCCS, Ist Oncol Veneto, Immunol and Mol Oncol Unit, Padua, Italy.
    Casella, Cinzia
    IRCCS, Ist Oncol Veneto, Immunol and Mol Oncol Unit, Padua, Italy.
    Imyanitov, Evgeny
    NN Petrov Institute Oncol, St Petersburg, Russia.
    Tihomirova, Laima
    Latvian Biomed Research and Study Centre, Riga, Latvia.
    Blanco, Ignacio
    Catalan Institute Oncol IDIBELL, Hereditary Canc Program, Barcelona, Spain.
    Lazaro, Conxi
    Catalan Institute Oncol IDIBELL, Hereditary Canc Program, Barcelona, Spain.
    J. Ramus, Susan
    University London Imperial Coll Science Technology and Med, Gynaecol Oncol Unit, UCL EGA Institute Womens Hlth, London, England.
    Sucheston, Lara
    Roswell Pk Canc Institute, Department Canc Prevent and Control, Buffalo, NY 14263 USA.
    Y. Karlan, Beth
    Cedars Sinai Med Centre, Womens Canc Research Institute, Samuel Oschin Comprehens Canc Institute, Los Angeles, CA 90048 USA.
    Gross, Jenny
    Cedars Sinai Med Centre, Womens Canc Research Institute, Samuel Oschin Comprehens Canc Institute, Los Angeles, CA 90048 USA.
    Schmutzler, Rita
    University Cologne, Centre Familial Breast and Ovarian Canc, Department Obstet and Gynaecol, Cologne, Germany.
    Wappenschmidt, Barbara
    University Cologne, Centre Familial Breast and Ovarian Canc, Department Obstet and Gynaecol, Cologne, Germany.
    Engel, Christoph
    University Leipzig, Institute Med Informat Stat and Epidemiol, Leipzig, Germany.
    Meindl, Alfons
    Tech University Munich, Klinikum Rechts Isar, Department Obstet and Gynaecol, Div Tumor Genet, D-8000 Munich, Germany.
    Lochmann, Magdalena
    Tech University Munich, Klinikum Rechts Isar, Department Obstet and Gynaecol, Div Tumor Genet, D-8000 Munich, Germany.
    Arnold, Norbert
    University Kiel, Department Obstet and Gynaecol, University Hospital Schleswig Holstein, Kiel, Germany.
    Heidemann, Simone
    University Kiel, Institute Human Genet, University Hospital Schleswig Holstein, Kiel, Germany.
    Varon-Mateeva, Raymonda
    Campus Virchow Klinikum, Charite Berlin, Institute Human Genet, Berlin, Germany.
    Niederacher, Dieter
    University Dusseldorf, Department Obstet and Gynaecol, Div Mol Genet, University Hospital Dusseldorf, Dusseldorf, Germany.
    Sutter, Christian
    University Heidelberg, Institute Human Genet, Div Mol Diagnost, Heidelberg, Germany.
    Deissler, Helmut
    University Hospital Ulm, Department Obstet and Gynaecol, Ulm, Germany.
    Gadzicki, Dorothea
    Hannover Med Sch, Institute Cell and Mol Pathol, D-3000 Hannover, Germany.
    Preisler-Adams, Sabine
    University Hospital Muenster, Institute Human Genet, Munster, Germany.
    Kast, Karin
    Tech University Dresden, Department Obstet and Gynaecol, University Hospital Carl Gustav Carus, Dresden, Germany.
    Schoenbuchner, Ines
    University Wurzburg, Institute Human Genet, Div Med Genet, Wurzburg, Germany.
    Caldes, Trinidad
    Hospital Clin San Carlos, Mol Oncol Lab, Madrid, Spain.
    de la Hoya, Miguel
    Hospital Clin San Carlos, Mol Oncol Lab, Madrid, Spain.
    Aittomaeki, Kristiina
    University Helsinki, Cent Hospital, Department Clin Genet, Helsinki, Finland.
    Nevanlinna, Heli
    University Helsinki, Cent Hospital, Department Obstet and Gynecol, FIN-00290 Helsinki, Finland.
    Simard, Jacques
    Centre Hospital University Quebec, Canada Research Chair Oncogenet, Canc Genom Lab, Quebec City, PQ, Canada.
    B. Spurdle, Amanda
    Queensland Institute Med Research, Brisbane, Qld, Australia.
    Holland, Helene
    Queensland Institute Med Research, Brisbane, Qld, Australia.
    Chen, Xiaoqing
    Queensland Institute Med Research, Brisbane, Qld, Australia.
    Platte, Radka
    Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    Chenevix-Trench, Georgia
    Queensland Institute of Medical Research, Brisbane, Australia.
    F. Easton, Douglas
    University Chicago, Med Centre, Chicago, IL 60637 USA.
    Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 23, p. 9742-9754Article in journal (Refereed)
    Abstract [en]

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03–1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01–1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10−11 − 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers. Cancer Res; 70(23); 9742–54. ©2010 AACR.

  • 2.
    Bendrik, Christina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Robertson, Jennifer
    Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics McMaster University, Hamilton, Ontario, Canada.
    Gauldie, Jack
    Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics McMaster University, Hamilton, Ontario, Canada.
    Dabrosin, Charlotta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Gene transfer of matrix metalloproteinase-9 induces tumor regression of breast cancer in vivo2008In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 68, no 9, p. 3405-3412Article in journal (Refereed)
    Abstract [en]

    Matrix metalloproteinases (MMP) are important regulators of angiogenesis and tumor progression by degradation of extracellular matrix. Clinical trials using MMP inhibitors have failed and recent studies suggest that MMPs may in contrast suppress tumor growth. It is not known, however, if MMPs or their inhibitors, tissue inhibitor of metalloproteinases (TIMP), can be used as therapy of established cancer. Here, adenovirus vectors carrying the human genes for MMP-9, TIMP-1, or empty controls were injected intratumorally in breast cancers established in mice supplemented with estradiol and treated with tamoxifen. Microdialysis was used to quantify MMP activity and sampling of endostatin and vascular endothelial growth factor (VEGF) in situ. We show that AdMMP-9 increased MMP activity in vivo, decreased tumor growth rate, and decreased microvessel area significantly. AdMMP-9 therapy resulted in significantly increased levels of endostatin in vivo, whereas VEGF levels were unaffected. As previously shown, tamoxifen exposure by itself increased MMP activity in all treatment groups. Moreover, the combined therapy with AdMMP-9 and tamoxifen further reduced tumor growth and increased the endostatin levels compared with either treatment alone. Gene transfer of TIMP-1 had no effects on tumor progression and counteracted the therapeutic effect of tamoxifen in our breast cancer model. This is the first report showing that overexpression of MMP-9 results in increased generation of antiangiogenic fragments, decreased angiogenesis, and therapeutic effects of established breast cancer.

  • 3.
    Busch, Susann
    et al.
    Gothenburg University, Sweden.
    Sims, Andrew H.
    University of Edinburgh, Scotland.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Ferno, Marten
    Lund University, Sweden.
    Landberg, Goran
    Gothenburg University, Sweden; University of Manchester, England.
    Loss of TGF beta Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 7, p. 1457-1469Article in journal (Refereed)
    Abstract [en]

    One third of the patients with estrogen receptor alpha (ER alpha)-positive breast cancer who are treated with the antiestrogen tamoxifen will either not respond to initial therapy or will develop drug resistance. Endocrine response involves crosstalk between ER alpha and TGF beta signaling, such that tamoxifen non-responsiveness or resistance in breast cancer might involve aberrant TGF beta signaling. In this study, we analyzed TGF beta receptor type 2 (TGFBR2) expression and correlated it with ER alpha status and phosphorylation in a cohort of 564 patients who had been randomized to tamoxifen or no-adjuvant treatment for invasive breast carcinoma. We also evaluated an additional four independent genetic datasets in invasive breast cancer. In all the cohorts we analyzed, we documented an association of low TGFBR2 protein and mRNA expression with tamoxifen resistance. Functional investigations confirmed that cell cycle or apoptosis responses to estrogen or tamoxifen in ER alpha-positive breast cancer cells were impaired by TGFBR2 silencing, as was ER alpha phosphorylation, tamoxifen-induced transcriptional activation of TGF beta, and upregulation of the multidrug resistance protein ABCG2. Acquisition of low TGFBR2 expression as a contributing factor to endocrine resistance was validated prospectively in a tamoxifen-resistant cell line generated by long-term drug treatment. Collectively, our results established a central contribution of TGF beta signaling in endocrine resistance in breast cancer and offered evidence that TGFBR2 can serve as an independent biomarker to predict treatment outcomes in ER alpha-positive forms of this disease.

  • 4. Dressman, Marlene
    et al.
    Baras, Alex
    Malinowski, Rachel
    Alvis, Lisa
    Kwon, Irene
    Walz, Thomas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Polymeropoulos, Mihael
    Gene expression profiling detects gene amplification and differentiates tumor types in breast cancer2003In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 63, p. 2194-2199Article in journal (Refereed)
  • 5.
    Fulda, S.
    et al.
    Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
    Friesen, C.
    Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
    Los, Marek Jan
    Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
    Scaffidi, C.
    Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
    Mier, W.
    Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
    Benedict, M.
    Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
    Nunez, G.
    Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
    Krammer, P. H.
    Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
    Peter, M. E.
    Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
    Debatin, K. M.
    Division of Hematology/Oncology, University Children's Hospital and Division of Molecular Oncology, German Cancer Research Center, Heidelberg, Germany; Divisions of Immunogenetics and Molecular Toxicology, German Cancer Research Center, Heidelberg, Germany; and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
    Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors1997In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 57, no 21, p. 4956-4964Article in journal (Refereed)
    Abstract [en]

    Betulinic acid CBA), a melanoma-specific cytotoxic agent, induced apoptosis in neuroectodermal tumors, such as neuroblastoma, medulloblastoma, and Ewing's sarcoma, representing the most common solid tumors of childhood. BA triggered an apoptosis pathway different from the one previously identified for standard chemotherapeutic drugs. BA-induced apoptosis was independent of CD95-ligand/receptor interaction and accumulation of wild-type p53 protein, but it critically depended on activation of caspases (interleukin 1 beta-converting enzyme/Ced-3-like proteases), FLICE/MACH (caspase-8), considered to be an upstream protease in the caspase cascade, and the downstream caspase CPP32/YAMA/Apopain (caspase-3) were activated, resulting in cleavage of the prototype substrate of caspases PARP. The broad-spectrum peptide inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, which blocked cleavage of FLICE and PARP, also completely abrogated BA-triggered apoptosis. Cleavage of caspases was preceded by disturbance of mitochondrial membrane potential and by generation of reactive oxygen species. Overexpression of Bcl-2 and Bcl-x(L) conferred resistance to BA at the level of mitochondrial dysfunction, protease activation, and nuclear fragmentation. This suggested that mitochondrial alterations were involved in BA-induced activation of caspases. Furthermore, pax and Bcl-x(s), two death-promoting proteins of the Bcl-2 family, were up-regulated following BA treatment. Most importantly, neuroblastoma cells resistant to CD95- and doxorubicin-mediated apoptosis were sensitive to treatment with BA, suggesting that BA may bypass some forms of drug resistance. Because BA exhibited significant antitumor activity on patients' derived neuroblastoma cells ex vivo, BA may be a promising new agent for the treatment of neuroectodermal tumors in vivo.

  • 6.
    Gunnarsson, Cecilia
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Olsson, Birgit
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Arnesson, Lars-Gunnar
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Abnormal expression of 17β-hydroxysteroid dehydrogenases in breast cancer predicts late recurrence2001In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 61, no 23, p. 8448-8451Article in journal (Refereed)
    Abstract [en]

    The 17β-hydroxysteroid dehydrogenase (17β-HSD) enzymes are involved in the interconversion of biologically active and inactive sex steroids and are considered to play a critical role in the in situ metabolism of estrogen, especially in estrogen-dependent breast cancer. The gene encoding 17β-HSD type 2 is located at 16q24.1-2, and earlier studies have shown that allelic loss in this region is an early and frequent event in breast cancer progression. Recurrence of hormone-dependent breast cancer frequently occurs several years after the primary treatment. The aim of this study was to investigate whether the expression of 17β-HSD types 1 and 2 differs in tumors from patients with late relapses (>5 years) compared with controls without recurrence after long-term follow-up. Using real-time reverse transcription-PCR, we found that the normal mammary gland expressed both 17β-HSD types 1 and 2, whereas the tumors frequently lacked detectable levels of type 2. Only 10% of the estrogen receptor-positive tumors expressed type 2, whereas 31% of the ERnegative tumors did so (P = 0.031). In a case-control series of 84 patients, a high level of 17β-HSD type 1 indicated increased risk to develop late relapse of breast cancer (odds ratio, 3.0; 95% confidence interval, 1.0–12.6; P = 0.041), whereas retained expression of type 2 indicated decreased risk (odds ratio, 0.25; 95% confidence interval, 0.05–1.2; P = 0.050). In multivariate analysis of the estrogen receptor-positive patients, the absence of 17β-HSD type 2 combined with a high expression of type 1 showed prognostic significance (P = 0.016) in addition to DNA aneuploidy (P = 0.0058), whereas progesterone receptor status did not (P = 0.71). These findings suggest that abnormal expression of 17β-HSD isoforms has prognostic significance in breast cancer and that altered expression of these enzymes may have importance in breast cancer progression.

  • 7.
    Jansson, Agneta
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Gunnarsson, Cecilia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Cohen, Maja
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Sivik, Tove
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    17β-hydroxysteroid dehydrogenase 14 affects estradiol levels in breast cancer cells and is a prognostic marker in estrogen receptor-positive breast cancer2006In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 66, no 23, p. 11471-11477Article in journal (Refereed)
    Abstract [en]

    Estrogens have an important role in the progression of breast cancer. The 17β-hydroxysteroid dehydrogenase (17HSD) family has been identified to be of significance in hormone-dependent tissues. 17HSD1 and 17HSD2 are the main 17HSD enzymes involved in breast cancer investigated this far, but it is possible that other hormone-regulating enzymes have a similar role. 17HSD5 and 17HSD12 are associated with sex steroid metabolism, and 17HSD14 is a newly discovered enzyme that may be involved in the estrogen balance. The mRNA expression of 17HSD5, 17HSD12, and 17HSD14 were analyzed in 131 breast cancer specimens by semiquantitative real-time PCR. The results were compared with recurrence-free survival and breast cancer-specific survival of the patients. The breast cancer cell lines MCF7, SKBR3, and ZR75-1 were transiently transfected with 17HSD14 to investigate any possible effect on estradiol levels. We found that high 17HSD5 was related to significantly higher risk of late relapse in estrogen receptor (ER)-positive patients remaining recurrence-free later than 5 years after diagnosis (P = 0.02). No relation to 17HSD12 expression was found, indicating that 17HSD12 is of minor importance in breast cancer. Patients with ER-positive tumors with high expression levels of 17HSD14 showed a significantly better prognosis about recurrence-free survival (P = 0.008) as well as breast cancer-specific survival (P = 0.01), confirmed by multivariate analysis (P = 0.04). Transfection of 17HSD14 in the human breast cancer cells MCF7 and SKBR3 significantly decreased the levels of estradiol, presenting an effect of high expression levels of the enzyme. ©2006 American Association for Cancer Research.

  • 8.
    Jia, Min
    et al.
    Karolinska Institute, Sweden.
    Andreassen, Trygve
    Norwegian University of Science and Technology, Norway.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology. Karolinska Institute, Sweden.
    Frost Bathen, Tone
    Norwegian University of Science and Technology, Norway.
    Sinha, Indranil
    Karolinska Institute, Sweden.
    Gao, Hui
    Karolinska Institute, Sweden.
    Zhao, Chunyan
    Karolinska Institute, Sweden.
    Haldosen, Lars-Arne
    Karolinska Institute, Sweden.
    Cao, Yihai
    Karolinska Institute, Sweden.
    Girnita, Leonard
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Andreas Moestue, Siver
    Norwegian University of Science and Technology, Norway.
    Dahlman-Wright, Karin
    Karolinska Institute, Sweden.
    Estrogen Receptor a Promotes Breast Cancer by Reprogramming Choline Metabolism2016In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 76, no 19, p. 5634-5646Article in journal (Refereed)
    Abstract [en]

    Estrogen receptor alpha (ER alpha) is a key regulator of breast growth and breast cancer development. Here, we report how ER alpha impacts these processes by reprogramming metabolism in malignant breast cells. We employed an integrated approach, combining genome-wide mapping of chromatin-bound ER alpha with estrogeninduced transcript and metabolic profiling, to demonstrate that ER alpha reprograms metabolism upon estrogen stimulation, including changes in aerobic glycolysis, nucleotide and amino acid synthesis, and choline (Cho) metabolism. Cho phosphotransfse CHPT1, identified as a direct era-regulated gene, was required for estrogen- induced effects on Cho metabolism, including increased phosphatidylcholine synthesis. CHPT1 silencing inhibited anchorage- independent growth and cell proliferation, also suppressing early-stage metastasis of tamoxifen-resistant breast cancer cells in a zebrafish xenograft model. Our results showed that era promotes metabolic alterations in breast cancer cells mediated by its target CHPT1, which this study implicates as a candidate therapeutic target. (C) 2016 AACR.

  • 9.
    Jirström, Karin
    et al.
    Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden.
    Stendahl, Maria
    Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden.
    Rydén, Lisa
    Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden.
    Kronblad, Åsa
    Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden.
    Bendahl, Pär-Ola
    Department of Oncology, University Hospital, Lund, Sweden.
    Stål, Olle
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Landberg, Göran
    Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden.
    Adverse effect of adjuvant tamoxifen in premenopausal breast cancer with cyclin D1 gene amplification2005In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 65, no 17, p. 8009-8016Article in journal (Refereed)
    Abstract [en]

    Cyclins D1 and A2 are cell cycle regulators that also have the ability to interact with the estrogen receptor (ER) and consequently interfere with antiestrogen treatment in breast cancer. Experimental data support this concept, but the clinical relevance needs to be further established. In this study, we evaluated cyclin D1 and A2 protein expression by immunohistochemistry and cyclin D1 gene (CCND1) amplification by fluorescence in situ hybridization in 500 primary breast cancers arranged in tissue microarrays. Patients had been randomized to 2 years of adjuvant tamoxifen or no treatment with a median follow-up of 14 years, allowing for subgroup analysis of treatment response defined by cyclin status. We found that both cyclin D1 and A2 protein overexpression was associated with an impaired tamoxifen response, although not significant in multivariate interaction analyses, whereas tamoxifen-treated patients with CCND1-amplified tumors had a substantially increased risk for disease recurrence after tamoxifen treatment in univariate analyses [relative risk (RR), 2.22; 95% confidence interval (95% CI), 0.94-5.26; P = 0.06] in contrast to nonamplified tumors (RR, 0.39; 95% CI, 0.23-0.65; P < 0.0001). Consequently, a highly significant interaction between tamoxifen treatment and CCND1 amplification could be shown regarding both recurrence-free survival (RR, 6.38; 95% CI, 2.29-17.78; P < 0.001) and overall survival (RR, 5.34; 95% CI, 1.84-15.51; P = 0.002), suggesting an agonistic effect of tamoxifen in ER-positive tumors. In node-positive patients, the disparate outcome according to gene amplification status was even more accentuated. In summary, our data implicate that despite a significant correlation to cyclin D1 protein expression, amplification status of the CCND1 gene seems a strong independent predictor of tamoxifen response, and possibly agonism, in premenopausal breast cancer.

  • 10.
    Karlsson, Jan-Olof G
    et al.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Brurok, H
    Norwegian University of Science and Technology.
    Towart, R
    Norwegian University of Science and Technology.
    Jynge, Per
    Norwegian University of Science and Technology.
    Letter: The magnetic resonance imaging contrast agent mangafodipir exerts antitumor activity via a previously described superoxide dismutase mimetic activity2006In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 66, no 1, p. 598-598Article in journal (Other academic)
    Abstract [en]

    n/a

  • 11.
    Lovejoy, David B
    et al.
    University of Sydney.
    Jansson, Patric J
    University of Sydney.
    Brunk, Ulf
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Wong, Jacky
    University of Sydney.
    Ponka, Prem
    Lady Davis Institute.
    Richardson, Des R
    University of Sydney.
    Antitumor Activity of Metal-Chelating Compound Dp44mT Is Mediated by Formation of a Redox-Active Copper Complex That Accumulates in Lysosomes2011In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 71, no 17, p. 5871-5880Article in journal (Refereed)
    Abstract [en]

    The metal-chelating compound Dp44mT is a di-2-pyridylketone thiosemicarbazone (DpT) which displays potent and selective antitumor activity. This compound is receiving translational attention, but its mechanism is poorly understood. Here, we report that Dp44mT targets lysosome integrity through copper binding. Studies using the lysosomotropic fluorochrome acridine orange established that the copper-Dp44mT complex (Cu[Dp44mT]) disrupted lysosomes. This targeting was confirmed with pepstatin A-BODIPY FL, which showed redistribution of cathepsin D to the cytosol with ensuing cleavage of the proapoptotic BH3 protein Bid. Redox activity of Cu[Dp44mT] caused cellular depletion of glutathione, and lysosomal damage was prevented by cotreatment with the glutathione precursor N-acetylcysteine. Copper binding was essential for the potent antitumor activity of Dp44mT, as coincubation with nontoxic copper chelators markedly attenuated its cytotoxicity. Taken together, our studies show how the lysosomal apoptotic pathway can be selectively activated in cancer cells by sequestration of redox-active copper. Our findings define a novel generalized strategy to selectively target lysosome function for chemotherapeutic intervention against cancer.

  • 12.
    Lundin, Anna-Carin
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Eriksson, Birgitta
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Bergman-Jungeström, Malin
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Wingren, Sten
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Association of breast cancer progression with a vitamin D receptor gene polymorphism1999In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 59, no 10, p. 2332-2334Article in journal (Refereed)
    Abstract [en]

    The vitamin D3 receptor gene (VDR) contains a TaqI RFLP that is associated with increased VDR mRNA stability, increased serum levels of 1α,25-dihydroxyvitamin D3 (1,25-D3), and decreased risk for prostate cancer. Determination of the TaqI genotype, in a group of young women with breast cancer (n = 111; age, <37 years) and a control population (n = 130), revealed no overall association to risk for breast cancer. However, patients without TaqI site (TT genotype) showed a significantly increased risk for lymph node metastasis (relative risk, 1.8, 95% confidence interval, 1.3- 2.6). Furthermore, a tendency toward an increased survival was found among estrogen receptor-positive, tamoxifen-treated patients who were homozygous for the TaqI site (P = 0.075). We conclude that polymorphism in the VDR gene may influence tumor progression and tamoxifen treatment response in early- onset breast carcinomas.

  • 13.
    Pena, Cristina
    et al.
    Karolinska Institute, Sweden .
    Virtudes Cespedes, Maria
    Centre Bioengn Biomat and Nanomed CIBER BBN, Spain .
    Bradic Lindh, Maja
    Karolinska Institute, Sweden .
    Kiflemariam, Sara
    Uppsala University, Sweden .
    Mezheyeuski, Artur
    Karolinska Institute, Sweden .
    Edqvist, Per-Henrik
    Uppsala University, Sweden .
    Hagglof, Christina
    Karolinska Institute, Sweden .
    Birgisson, Helgi
    Uppsala University, Sweden .
    Bojmar, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Jirstrom, Karin
    Lund University, Sweden .
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Olsson, Eleonor
    Lund University, Sweden .
    Veerla, Srinivas
    Lund University, Sweden .
    Gallardo, Alberto
    Centre Bioengn Biomat and Nanomed CIBER BBN, Spain .
    Sjoblom, Tobias
    Uppsala University, Sweden .
    Chang, AndyC -M
    University of Sydney, Australia .
    Reddel, Roger R.
    University of Sydney, Australia .
    Mangues, Ramon
    Centre Bioengn Biomat and Nanomed CIBER BBN, Spain .
    Augsten, Martin
    Karolinska Institute, Sweden .
    Ostman, Arne
    Karolinska Institute, Sweden .
    STC1 Expression By Cancer-Associated Fibroblasts Drives Metastasis of Colorectal Cancer2013In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 4, p. 1287-1297Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor (PDGF) receptor signaling is a major functional determinant of cancer-associated fibroblasts (CAF). Elevated expression of PDGF receptors on stromal CAFs is associated with metastasis and poor prognosis, but mechanism(s) that underlie these connections are not understood. Here, we report the identification of the secreted glycoprotein stanniocalcin-1 (STC1) as a mediator of metastasis by PDGF receptor function in the setting of colorectal cancer. PDGF-stimulated fibroblasts increased migration and invasion of cocultured colorectal cancer cells in an STC1-dependent manner. Analyses of human colorectal cancers revealed significant associations between stromal PDGF receptor and STC1 expression. In an orthotopic mouse model of colorectal cancer, tumors formed in the presence of STC1-deficient fibroblasts displayed reduced intravasation of tumor cells along with fewer and smaller distant metastases formed. Our results reveal a mechanistic basis for understanding the contribution of PDGF-activated CAFs to cancer metastasis. Cancer Res; 73(4); 1287-97.

  • 14.
    Plaza Menacho, Ivan
    et al.
    University of Groningen, the Netherlands.
    Koster, Roelof
    University of Groningen, the Netherlands.
    van der Sloot, Almer
    University of Groningen, the Netherlands.
    Quax, Wim
    University of Groningen, the Netherlands.
    Osinga, Jan
    University of Groningen, the Netherlands.
    van der Sluis, Tineke
    University of Groningen, the Netherlands.
    Hollema, Harry
    University of Groningen, the Netherlands.
    Burzynski, Grzegorz
    University of Groningen, the Netherlands.
    Gimm, Oliver
    Martin-Luther-University, Halle-Wittenberg, Germany.
    Buys, Charles
    University of Groningen, the Netherlands.
    Eggen, Bart
    University of Groningen, the Netherlands.
    Hofstra, Robert
    University of Groningen, the Netherlands.
    RET-familial medullary thyroid carcinoma mutants Y791F and S891A activate a Src/JAK/STAT3 pathway, independent of glial cell line-derived neurotrophic factor2005In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 65, no 5, p. 1729-1737Article in journal (Refereed)
    Abstract [en]

    The RET proto-oncogene encodes a receptor tyrosine kinase whose dysfunction plays a crucial role in the development of several neural crest disorders. Distinct activating RET mutations cause multiple endocrine neoplasia type 2A (MEN2A), type 2B (MEN2B), and familial medullary thyroid carcinoma (FMTC). Despite clear correlations between the mutations found in these cancer syndromes and their phenotypes, the molecular mechanisms connecting the mutated receptor to the different disease phenotypes are far from completely understood. Luciferase reporter assays in combination with immunoprecipitations, and Western and immunohistochemistry analyses were done in order to characterize the signaling properties of two FMTC-associated RET mutations, Y791F and S891A, respectively, both affecting the tyrosine kinase domain of the receptor. We show that these RET-FMTC mutants are monomeric receptors which are autophosphorylated and activated independently of glial cell line-derived neurotrophic factor. Moreover, we show that the dysfunctional signaling properties of these mutants, when compared with wild-type RET, involve constitutive activation of signal transducers and activators of transcription 3 (STAT3). Furthermore, we show that STAT3 activation is mediated by a signaling pathway involving Src, JAK1, and JAK2, differing from STAT3 activation promoted by RET(C634R) which was previously found to be independent of Src and JAKs. Three-dimensional modeling of the RET catalytic domain suggested that the structural changes promoted by the respective amino acids substitutions lead to a more accessible substrate and ATP-binding monomeric conformation. Finally, immunohistochemical analysis of FMTC tumor samples support the in vitro data, because nuclear localized, Y705-phosphorylated STAT3, as well as a high degree of RET expression at the plasma membrane was observed.

  • 15.
    Shukla, Neerav
    et al.
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Somwar, Romel
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Smith, Roger S.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Ambati, Sri
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Munoz, Stanley
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Merchant, Melinda
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    D´arcy, Padraig
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Wang, Xin
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Kobos, Rachel
    Mem Sloan Kettering Cancer Centre, NY 10065 USA.
    Antczak, Christophe
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Bhinder, Bhavneet
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Shum, David
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Radu, Constantin
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Yang, Guangbin
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Taylor, Barry S.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA; Mem Sloan Kettering Cancer Centre, NY 10021 USA; Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Ng, Charlotte K. Y.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Weigelt, Britta
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Khodos, Inna
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    de Stanchina, Elisa
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Reis-Filho, Jorge S.
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Ouerfelli, Ouathek
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Linder, Stig
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden.
    Djaballah, Hakim
    Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Ladanyi, Marc
    Mem Sloan Kettering Cancer Centre, NY 10021 USA; Mem Sloan Kettering Cancer Centre, NY 10021 USA.
    Proteasome Addiction Defined in Ewing Sarcoma Is Effectively Targeted by a Novel Class of 19S Proteasome Inhibitors2016In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 76, no 15, p. 4525-4534Article in journal (Refereed)
    Abstract [en]

    Ewing sarcoma is a primitive round cell sarcoma with a peak incidence in adolescence that is driven by a chimeric oncogene created from the fusion of the EWSR1 gene with a member of the ETS family of genes. Patients with metastatic and recurrent disease have dismal outcomes and need better therapeutic options. We screened a library of 309,989 chemical compounds for growth inhibition of Ewing sarcoma cells to provide the basis for the development of novel therapies and to discover vulnerable pathways that might broaden our understanding of the pathobiology of this aggressive sarcoma. This screening campaign identified a class of benzyl-4-piperidone compounds that selectively inhibit the growth of Ewing sarcoma cell lines by inducing apoptosis. These agents disrupt 19S proteasome function through inhibition of the deubiquitinating enzymes USP14 and UCHL5. Functional genomic data from a genome-wide shRNA screen in Ewing sarcoma cells also identified the proteasome as a node of vulnerability in Ewing sarcoma cells, providing orthologous confirmation of the chemical screen findings. Furthermore, shRNA-mediated silencing of USP14 or UCHL5 in Ewing sarcoma cells produced significant growth inhibition. Finally, treatment of a xenograft mouse model of Ewing sarcoma with VLX1570, a benzyl-4-piperidone compound derivative currently in clinical trials for relapsed multiple myeloma, significantly inhibited in vivo tumor growth. Overall, our results offer a preclinical proof of concept for the use of 19S proteasome inhibitors as a novel therapeutic strategy for Ewing sarcoma. (C) 2016 AACR.

  • 16.
    Spyrou, Giannis
    et al.
    Karolinska Institutet, Stockholm, Sweden. .
    Björnstedt, M.
    Karolinska Institutet, Stockholm, Sweden.
    Skog, S.
    Karolinska Institutet, Stockholm, Sweden.
    Holmgren, A.
    Karolinska Institutet, Stockholm, Sweden.
    Selenite and selenate inhibit human lymphocyte growth via different mechanisms1996In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 56, no 19, p. 4407-4412Article in journal (Refereed)
    Abstract [en]

    Selenium compounds like selenite and selenate have strong inhibitory effects, particularly on mammalian tumor cell growth by unknown mechanisms. We found that the addition of sodium selenite and sodium selenate inhibited the growth of human 3B6 and BL41 lymphocytes. Selenite was more potent because 10 microM selenite produced a growth inhibitory effect similar to that of 250 microM selenate. The mechanism of action of selenite and selenate appears to be different. 3B6 and BL41 cells treated with selenite accumulated in the S-phase; however, selenate caused an accumulation of cells in G2. Selenite-mediated growth inhibition was irreversible, although the effects of selenate could be reversed. Selenite, in contrast to selenate, is efficiently reduced by the thioredoxin system (thioredoxin, thioredoxin reductase, and NADPH). At concentrations required to observe a similar effect on cell growth, the activity of thioredoxin reductase, recently shown to be a selenoprotein, increased in selenite-treated cells and decreased in selenate-treated cells. Ribonucleotide reductase activity was inhibited in an in vitro assay by selenite and selenodiglutathione but not by selenate. These results show that selenite and selenate use different mechanisms to inhibit cell growth.

  • 17.
    Söderberg, Anita
    et al.
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Sahaf, Bita
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Rosén, Anders
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Thioredoxin Reductase, a Redox-active Selenoprotein, Is Secreted by Normal and Neoplastic Cells: Presence in Human Plasma2000In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 60, no 8, p. 2281-2289Article in journal (Refereed)
    Abstract [en]

    Thioredoxin (Trx) and Trx reductase (TrxR) are redox-active proteins that participate in multiple cellular events, including growth promotion, apoptosis, and cytoprotection. Studies on overexpression of Trx and TrxR in human cancers have indicated a role of these proteins in tumor development. In this study, we analyzed the expression of TrxR in peripheral blood cells, tumor-transformed leukemia, and melanoma cells and found, in addition to abundant plasma membrane localization, that TrxR was released from these cells. Secretory cells were observed at the single cell level using a sensitive enzyme-linked immunospot assay. The release was inducible, and physiological stimulation of human monocytes by IFN-γ, lipopolysaccharide, and interleukin 1α significantly increased the number of TrxR-secreting cells (P = 0.004). Secretion of TrxR followed the classical Golgi pathway, and it was confirmed by metabolic labeling using [35S]methionine and[ 35S]cysteine. TrxR was also detected for the first time in fresh healthy blood donor plasma (n = 21; median concentration, 18.0 ng/ml), with biological activity as determined by insulin reduction assay.

    These results highlight the role of extracellular Trx and TrxR during inflammation and tumor progression. Released Trx, with its active site motif containing amino acids Cys-X-X-Cys, was recently shown to have chemoattractant properties beside its previously described antioxidant and cocytokine activities. Regeneration of oxidized Trx requires available TrxR outside the cell, the presence and induction of which is described in this paper for normal and transformed cells.

  • 18.
    Udumyan, Ruzan
    et al.
    Örebro University, Sweden.
    Montgomery, Scott
    Örebro University, Sweden; Karolinska University Hospital, Sweden; UCL, England.
    Fang, Fang
    Karolinska Institute, Sweden.
    Almroth, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Valdimarsdottir, Unnur
    Karolinska Institute, Sweden; University of Iceland, Iceland; Harvard School Public Heatlh, MA USA.
    Ekbom, Anders
    Karolinska University Hospital, Sweden.
    Smedby, Karin E.
    Karolinska University Hospital, Sweden; Karolinska University Hospital, Sweden.
    Fall, Katja
    Örebro University, Sweden; Karolinska Institute, Sweden.
    Beta-Blocker Drug Use and Survival among Patients with Pancreatic Adenocarcinoma2017In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, no 13, p. 3700-3707Article in journal (Refereed)
    Abstract [en]

    Preclinical studies have suggested that beta-adrenergic signaling is involved in pancreatic cancer progression. Prompted by such studies, we investigated an association between beta-blocker drug use with improved cancer-specific survival in a large, general population-based cohort of patients with pancreatic ductal adenocarcinoma (PDAC). All patients diagnosed with a first primary PDAC in Sweden between 2006 and 2009 were identified through the Swedish Cancer Register (n = 2,394). We obtained information about use of beta-blockers and other medications through linkage with the national Prescribed Drug Register. Cancer-specific mortality was assessed using the Swedish Cause of Death Register. We used multivariable Cox regression adjusted for sociodemographic factors, tumor characteristics, comorbidity score, and other medications to estimate HRs and 95% confidence intervals (CI) for cancer-specific mortality associated with beta-blocker use during the 90-day period before cancer diagnosis. A total of 2,054 (86%) died, with pancreatic cancer recorded as the underlying cause of death during a maximum of 5-year follow-up (median 5 months). Patients who used beta-blockers (n = 522) had a lower cancer-specific mortality rate than nonusers (adjusted HR, 0.79; 95% CI, 0.70-0.90; P amp;lt; 0.001). This observed rate reduction was more pronounced among patients with localized disease at diagnosis (n = 517; adjusted HR, 0.60; 95% CI, 0.43-0.83; P = 0.002), especially for users with higher daily doses (HR, 0.54; 95% CI, 0.35-0.83; P = 0.005). No clear rate differences were observed by beta-blocker receptor selectivity. Our results support the concept that beta-blocker drugs may improve the survival of PDAC patients, particularly among those with localized disease. (C) 2017 AACR.

  • 19.
    Wang, Jian
    et al.
    Karolinska Institute, Sweden; Shandong University, Peoples R China.
    Cao, Ziquan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Zhang, Xing-Mei
    Karolinska Institute, Sweden.
    Nakamura, Masaki
    Karolinska Institute, Sweden.
    Sun, Meili
    Karolinska Institute, Sweden; Shandong University, Peoples R China.
    Hartman, Johan
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Harris, Robert A.
    Karolinska Institute, Sweden.
    Sun, Yuping
    Shandong University, Peoples R China.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden; University of Leicester, England; Glenfield Hospital, England.
    Novel Mechanism of Macrophage-Mediated Metastasis Revealed in a Zebrafish Model of Tumor Development2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 2, p. 306-315Article in journal (Refereed)
    Abstract [en]

    Cancer metastasis can occur at early stages of tumor development due to facilitative alterations in the tumor microenvironment. Although imaging techniques have considerably improved our understanding of metastasis, early events remain challenging to study due to the small numbers of malignant cells involved that are often undetectable. Using a novel zebrafish model to investigate this process, we discovered that tumor-associated macrophages (TAM) acted to facilitate metastasis by binding tumor cells and mediating their intravasation. Mechanistic investigations revealed that IL6 and TNF alpha promoted the ability of macrophages to mediate this step. M2 macro-phages were particularly potent when induced by IL4, IL10, and TGF beta. In contrast, IFN gamma-lipopolysaccharide-induced M1 macrophages lacked the capability to function in the same way in the model. Confirming these observations, we found that human TAM isolated from primary breast, lung, colorectal, and endometrial cancers exhibited a similar capability in invasion and metastasis. Taken together, our work shows how zebrafish can be used to study how host contributions can facilitate metastasis at its earliest stages, and they reveal a new macrophage-dependent mechanism of metastasis with possible prognostic implications.

  • 20.
    Zhao, Chunyan
    et al.
    Department of Biosciences and Nutrition, Novum, Karolinska Institute, Huddinge, Sweden.
    Qiao, Yichun
    Department of Biosciences and Nutrition, Novum, Karolinska Institute, Huddinge, Sweden.
    Jonsson, Philip
    University of Houston, Texas, USA.
    Wang, Jian
    Karolinska Institute, Stockholm, Sweden .
    Xu, Li
    Department of Biosciences and Nutrition, Novum, Karolinska Institute, Huddinge, Sweden.
    Rouhi, Pegah
    Karolinska Institute, Stockholm, Sweden .
    Sinha, Indranil
    Department of Biosciences and Nutrition, Novum, Karolinska Institute, Huddinge, Sweden.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Karolinska Institute, Stockholm, Sweden; University of Leicester, Glenfield Hospital, Leicester, UK.
    Williams, Cecilia
    University of Houston, TX, USA .
    Dahlman-Wright, Karin
    Department of Biosciences and Nutrition, Novum, Karolinska Institute, Huddinge, Sweden.
    Genome-wide profiling of AP-1-regulated transcription provides insights into the invasiveness of triple-negative breast cancer2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 14, p. 3983-3994Article in journal (Refereed)
    Abstract [en]

    Triple-negative breast cancer (TNBC) is an aggressive clinical subtype accounting for up to 20% of all breast cancers, but its malignant determinants remain largely undefined. Here, we show that in TNBC the overexpression of Fra-1, a component of the transcription factor AP-1, offers prognostic potential. Fra-1 depletion or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes of TNBC cells in vitro. Similarly, RNAi-mediated attenuation of Fra-1 or c-Jun reduced cellular invasion in vivo in a zebrafish tumor xenograft model. Exploring the AP-1 cistrome and the AP-1-regulated transcriptome, we obtained insights into the transcriptional regulatory networks of AP-1 in TNBC cells. Among the direct targets identified for Fra-1/c-Jun involved in proliferation, adhesion, and cell-cell contact, we found that AP-1 repressed the expression of E-cadherin by transcriptional upregulation of ZEB2 to stimulate cell invasion. Overall, this work illuminates the pathways through which TNBC cells acquire invasive and proliferative properties.

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