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
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Carol Ward1, James Meehan1, Peter Mullen2, Claudiu Supuran3, J. Michael Dixon4, Jeremy S. Thomas5, Jean-Yves Winum6, Philippe Lambin7, Ludwig Dubois7, Nanda-Kumar Pavathaneni6,7, Edward J. Jarman1, Lorna Renshaw4, InHwa Um2, Charlene Kay1, David J. Harrison2, Ian H. Kunkler8, Simon P. Langdon1
1Division of Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
2School of Medicine, University of St Andrews, North Haugh, St Andrews, United Kingdom
3Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Sesto Fiorentino, Florence, Italy
4Edinburgh Breast Unit, Western General Hospital, Edinburgh, United Kingdom
5Department of Pathology, Western General Hospital, Edinburgh, United Kingdom
6Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS-UM1-UM2, Batiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier, Montpellier, France
7Department of Radiation Oncology (MaastRO), GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands
8Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
Carol Ward, e-mail: [email protected]
Keywords: carbonic anhydrase IX, breast cancer, tumour microenvironment, invasion, hypoxia
Received: May 11, 2015 Accepted: June 22, 2015 Published: July 04, 2015
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.
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