Sodium accumulation in breast cancer predicts malignancy and treatment response

TY - JOUR

T1 - Sodium accumulation in breast cancer predicts malignancy and treatment response

AU - James, Andrew D

AU - Leslie, Theresa K

AU - Kaggie, Joshua D

AU - Wiggins, Laura

AU - Patten, Lewis

AU - Murphy O'Duinn, John

AU - Langer, Swen

AU - Labarthe, Marie-Christine

AU - Riemer, Frank

AU - Baxter, Gabrielle

AU - McLean, Mary A

AU - Gilbert, Fiona J

AU - Kennerley, Aneurin J

AU - Brackenbury, William J

N1 - © 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).

PY - 2022/7/20

Y1 - 2022/7/20

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85128625123&partnerID=8YFLogxK

U2 - 10.1038/s41416-022-01802-w

DO - 10.1038/s41416-022-01802-w

M3 - Article

C2 - 35462561

SN - 0007-0920

VL - 127

SP - 337

EP - 349

JO - British journal of cancer

JF - British journal of cancer

ER -