Sodium accumulation in breast cancer predicts malignancy and treatment response

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.