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.
Highlights
A recent analysis by over 100 breast cancer specialists emphasized critical gaps in research knowledge needed to increase the successful treatment of breast cancer
To address several of these issues, we examined the effect of novel inhibitors of carbonic anhydrase IX (CAIX), an enzyme involved in pH regulation, on breast cancer growth and invasion using a series of increasingly complex models
We examined the effects of these inhibitors in an expanded panel of breast cancer cell lines (Supplementary Table S1) representing the major breast cancer subtypes, with variable hormone and growth factor receptor expression
Summary
A recent analysis by over 100 breast cancer specialists emphasized critical gaps in research knowledge needed to increase the successful treatment of breast cancer. Novel therapies for metastatic and triple negative breast cancer and better experimental models that encompass breast cancer subtypes were amongst the factors highlighted [1]. To address several of these issues, we examined the effect of novel inhibitors of carbonic anhydrase IX (CAIX), an enzyme involved in pH regulation, on breast cancer growth and invasion using a series of increasingly complex models. Dysregulation of tumor suppressors, oncogenes and growth factor receptor number increase the expression of HIF-1α and up-regulation of transcriptional targets in normoxic cancer cells [5, 6]. In breast cancer, increased HIF-1α expression is associated with poor prognosis, since HIF-1 controls expression of proteins required for surviva in hypoxic and acidic conditions [7, 8]
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