Sodium accumulation in breast cancer predicts malignancy and treatment response
Andrew D. James, Theresa K. Leslie, Joshua Kaggie, L. F. Wiggins, Lewis Patten, John Murphy O’Duinn, Swen Langer, Marie‐Christine Labarthe, Frank Riemer, Gabrielle Baxter, Mary A. McLean, Fiona J. Gilbert, Aneurin J. Kennerley, William J. Brackenbury
Abstract
Abstract Background Breast cancer remains a leading cause of death in women and novel imaging biomarkers are urgently required. Here, we demonstrate the diagnostic and treatment-monitoring potential of non-invasive sodium ( 23 Na) MRI in preclinical models of breast cancer. Methods Female Rag2 −/− Il2rg −/− and Balb/c mice bearing orthotopic breast tumours (MDA-MB-231, EMT6 and 4T1) underwent MRI as part of a randomised, controlled, interventional study. Tumour biology was probed using ex vivo fluorescence microscopy and electrophysiology. Results 23 Na MRI revealed elevated sodium concentration ([Na + ]) in tumours vs non-tumour regions. Complementary proton-based diffusion-weighted imaging (DWI) linked elevated tumour [Na + ] to increased cellularity. Combining 23 Na MRI and DWI measurements enabled superior classification accuracy of tumour vs non-tumour regions compared with either parameter alone. Ex vivo assessment of isolated tumour slices confirmed elevated intracellular [Na + ] ([Na + ] i ); extracellular [Na + ] ([Na + ] e ) remained unchanged. Treatment with specific inward Na + conductance inhibitors (cariporide, eslicarbazepine acetate) did not affect tumour [Na + ]. Nonetheless, effective treatment with docetaxel reduced tumour [Na + ], whereas DWI measures were unchanged. Conclusions Orthotopic breast cancer models exhibit elevated tumour [Na + ] that is driven by aberrantly elevated [Na + ] i . Moreover, 23 Na MRI enhances the diagnostic capability of DWI and represents a novel, non-invasive biomarker of treatment response with superior sensitivity compared to DWI alone.