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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

Research output: Contribution to journalArticle

Author(s)

Carol Ward, James Meehan, Peter Mullen, Claudiu Supuran, J. Michael Dixon, Jeremy S. Thomas, Jean-Yves Winum, Philippe Lambin, Ludwig Dubois, Nanda-Kumar Pavathaneni, Edward J. Jarman, Lorna Renshaw, In Hwa Um, Charlene Kay, David James Harrison, Ian H. Kunkler, Simon P. Langdon

School/Research organisations

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.

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Details

Original languageEnglish
Pages (from-to)24865-24870
Number of pages15
JournalOncotarget
Volume6
Issue number28
Early online date4 Jul 2015
Publication statusPublished - 2015

    Research areas

  • Carbonic anhydrase IX, Breast cancer, Tumour microenvironment, Invasion, Hypoxia

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ID: 195547268