title: Evaluation of carbonic anhydrase IX as a therapeutic target for inhibition of breast cancer invasion and metastasis using a series of in vitro breast cancer models.
abstract: Triple negative, resistant or metastatic disease are major factors in breast cancer mortality, warranting novel approaches. Carbonic anhydrase IX (CAIX) is implicated in survival, migration and invasion of breast cancer cells and inhibition provides an innovative therapeutic strategy. The efficacy of 5 novel ureido-substituted sulfamate CAIX inhibitors were assessed in increasingly complex breast cancer models, including cell lines in normoxia and hypoxia, 3D spheroids and an ex-vivo explant model utilizing fresh biopsy tissue from different breast cancer subtypes. CAIX expression was evaluated in a tissue microarray (TMA) of 92 paired lymph node and primary breast cancers and 2 inhibitors were appraised in vivo using MDA-MB-231 xenografts. FC11409B, FC9398A, FC9403, FC9396A and S4 decreased cell proliferation and migration and inhibited 3D spheroid invasion. S4, FC9398A and FC9403A inhibited or prevented invasion into collagen. FC9403A significantly reversed established invasion whilst FC9398A and DTP348 reduced xenograft growth. TMA analysis showed increased CAIX expression in triple negative cancers. These data establish CAIX inhibition as a relevant therapeutic goal in breast cancer, targeting the migratory, invasive, and metastatic potential of this disease. The use of biopsy tissue suggests efficacy against breast cancer subtypes, and should provide a useful tool in drug testing against invasive cancers.
authors.affiliation: Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Carol
authors.initials: C
authors.lastname: Ward
authors.affiliation: Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Meehan
authors.affiliation: School of Medicine, University of St Andrews, North Haugh, St Andrews, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Mullen
authors.affiliation: Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Sesto Fiorentino, Florence, Italy.
authors.forename: Claudiu
authors.initials: C
authors.lastname: Supuran
authors.affiliation: Edinburgh Breast Unit, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Dixon
authors.affiliation: Department of Pathology, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Thomas
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS-UM1-UM2, Batiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier, Montpellier, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Winum
authors.affiliation: Department of Radiation Oncology (MaastRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lambin
authors.affiliation: Department of Radiation Oncology (MaastRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Dubois
authors.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS-UM1-UM2, Batiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier, Montpellier, France.|Department of Radiation Oncology (MaastRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands.
authors.forename: Nanda-Kumar
authors.initials: NK
authors.lastname: Pavathaneni
authors.affiliation: Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Jarman
authors.affiliation: Edinburgh Breast Unit, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Lorna
authors.initials: L
authors.lastname: Renshaw
authors.affiliation: School of Medicine, University of St Andrews, North Haugh, St Andrews, United Kingdom.
authors.forename: In Hwa
authors.initials: IH
authors.lastname: Um
authors.affiliation: Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Charlene
authors.initials: C
authors.lastname: Kay
authors.affiliation: School of Medicine, University of St Andrews, North Haugh, St Andrews, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Harrison
authors.affiliation: Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Ian H
authors.initials: IH
authors.lastname: Kunkler
authors.affiliation: Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Langdon
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008819:Mice, Nude; D015394:Molecular Structure; D058990:Molecular Targeted Therapy / Q000379:methods*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000201:enzymology; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases
keywords: breast cancer; carbonic anhydrase IX; hypoxia; invasion; tumour microenvironment