Early detection of aggressive forms of breast cancer through non-invasive diagnostics is the best weapon in our arsenal against the leading cause of cancer-related deaths in women, worldwide.

In a new study on mice, researchers from the universities of York and Cambridge, U.K., have developed a new sodium magnetic resonance imaging (MRI) technique to detect levels of 23Na in breast tumors, that could help diagnose and monitor breast cancer, and indicate the degree of aggressiveness of a tumor and its susceptibility to chemotherapy.

William Brackenbury, PhD, a lecturer from the department of biology at the University of York is the senior author of the study.

“It’s a new way of imaging breast tumors, a variation on MRI, where we’re looking at the levels of sodium or salt within tumors. What’s novel about this study is we’ve been looking at where the sodium is in the tumor and trying to understand what it’s doing. We think it’s inside the cancer cells and may be playing an important role in regulating their activity,” said senior author William Brackenbury, PhD, from the department of biology at the University of York.

The study was published on April 25, 2022, in the British Journal of Cancer, in an article titled “Sodium accumulation in breast cancer predicts malignancy and treatment response.”

“We demonstrate the diagnostic and treatment-monitoring potential of non-invasive sodium (23Na) MRI in preclinical models of breast cancer,” the authors noted. Using the new technique, the researchers found sodium accumulates inside cancer cells and more active tumors accumulate more sodium.

Through complementary proton-based diffusion-weighted imaging (DWI), the investigators showed increased sodium concentrations in the cancer cells was linked to an increase in the number of cells in the tumors. Combining the two method, sodium MRI and DWI, the researchers could distinguish tumor versus non-tumor regions to a higher degree of accuracy than using either method alone.

Ex vivo assays on isolated tumor slices allowed the team to confirm that sodium ion levels within cancer cells alone increased while the levels outside the cancer cells were not affected.

“Sodium moves in and out of cells through ion channels and transporters. For a number of years, we’ve been studying one type of sodium channels called voltage-gated sodium channels. We found the expression of these channels increased on breast cancer cells compared with healthy cells,” said Brackenbury.

Brackenbury says a potential reason for the increased sodium in the breast cancer cells could be triggered by aberrant functions of sodium channel proteins on these cancer cells. In addition, since earlier studies have shown that the levels of sodium and the activity of these channels control cell proliferation and invasiveness, it is possible that targeting sodium transport through these channels could have therapeutic value.

Using the common chemotherapy drug, docetaxel, said Brackenbury, “slowed the growth of the tumors in mice and also reduced the sodium levels in the tumor cells.” DWI measures were unchanged upon docetaxel treatment.

Some early evidence from breast cancer patients shows a similar trend. “This suggests,” said Brackenbury, “sodium MRI could be a good but underutilized biomarker of response to chemotherapy.”

He added, “We’ve known for a while that solid tumors are high in salt, but this research brings us a step closer to understanding why. Our findings show that the high levels of sodium in breast tumors is coming from inside the cancer cells rather than the surrounding tissue fluid, meaning that there is something strange about their metabolic activity which leads to them accumulating more salt than healthy cells do.”

To understand which of the sodium transport proteins were playing a role in regulating sodium in the tumor cells, the team used the drug cariporide to inhibit a sodium-proton exchanger protein and the drug eslicarbazepine acetate to inhibit a voltage-gated sodium channel protein.

“We found those drugs didn’t affect the total sodium levels in the tumors,” said Brackenbury. “We interpret that to mean that the total level of sodium within the tumors, even if it’s intracellular, is probably dependent on the activity of multiple different types of sodium channels. So, if you target just one, the MRI is not sensitive enough to detect any change in sodium.”

Future work needs to focus on parsing out which sodium channels are responsible for the increased sodium levels in tumor cells, Brackenbury indicated.

His team is also using different tools—new radiofrequency coils and cooling systems–to improve the signal-to-noise ratio of the sodium MRI images which currently are relatively pixelated in comparison to normal MRI scans. The team is also conducting an observational study to see if their results can be replicated in human breast cancer patients.

Based on their findings, the authors claim, there is a potential for the development of drugs to block sodium channels in cancer cells that will slow the growth and metastasis of breast cancers.

Fiona Gilbert, MD, a professor of radiology at the University of Cambridge and a co-author of the study said, “We are excited about using these techniques in the clinic.”

Charles Evans, PhD, Research Information Manager at Cancer Research UK, said, “This interesting study demonstrates that using sodium MRI could be a powerful new way to improve detection of breast cancers. The technique also holds the potential to provide us with deeper insights into how breast cancers respond to treatments. What’s more, these techniques could be applied to other cancer types. The study is at an early stage, however, and more research will be needed before sodium MRI can begin to benefit patients.”’

“It’s vital breast cancer is diagnosed quickly and accurately, and its response to treatment closely monitored, to ensure patients receive the best possible care. This innovative early-stage research into sodium MRI has the potential to improve patient care, giving medical teams more in-depth information,” said Simon Vincent, PhD, director of research, support, and influencing at Breast Cancer Now.

Vincent added, “We look forward to scientists building on this discovery to understand how it can work in practice to benefit patients in the clinic. The way that breast cancer can accumulate sodium should also be investigated further as it may help discover new ways to treat this devastating disease.”

The study was funded by the charities Cancer Research UK and Breast Cancer Now, and Engineering and Physical Sciences Research Council (EPSRC) and Biotechnology and Biological Sciences Research Council (BBSRC).

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