Sodium accumulation in breast cancer predicts malignancy and treatment response

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 (²³Na) MRI in preclinical models of breast cancer.

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.

²³Na 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 ²³Na 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.

Orthotopic breast cancer models exhibit elevated tumour [Na⁺] that is driven by aberrantly elevated [Na⁺]_i. Moreover, ²³Na MRI enhances the diagnostic capability of DWI and represents a novel, non-invasive biomarker of treatment response with superior sensitivity compared to DWI alone.