Sodium accumulation in breast cancer predicts malignancy and treatment response

Andrew D James, Theresa K Leslie, Joshua D Kaggie, Laura 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

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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.

Original languageEnglish
Pages (from-to)337–349
Number of pages13
JournalBritish journal of cancer
Early online date25 Apr 2022
Publication statusPublished - 20 Jul 2022

Bibliographical note

© 2022, The Author(s).

Funding Information:
This work was supported by Cancer Research UK (A25922), Breast Cancer Now (2015NovPhD572), BBSRC (BB/S507416/1) and an EPSRC Impact Accelerator Award. FJG, JK, GB, MAM are supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

Publisher Copyright:
© 2022, The Author(s).

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