Sodium accumulation in breast cancer predicts malignancy and treatment response

James, AD ORCID: https://orcid.org/0000-0002-2432-5948, Leslie, TK, Kaggie, JD, Wiggins, L, Patten, L, Murphy O’Duinn, J, Langer, S, Labarthe, MC, Riemer, F, Baxter, G, McLean, MA, Gilbert, FJ, Kennerley, AJ ORCID: https://orcid.org/0000-0002-7599-7461 and Brackenbury, WJ ORCID: https://orcid.org/0000-0001-6882-3351 (2022) Sodium accumulation in breast cancer predicts malignancy and treatment response. British Journal of Cancer, 127 (2). pp. 337-349. ISSN 0007-0920

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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 (23Na) 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: 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. Conclusions: 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.