Sodium accumulation in breast cancer predicts malignancy and treatment response

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.