Sugar uptake & breast cancer

These phase contrast and confocal immunofluorescence images (inset) show 3D cultures of non-malignant (S1) and malignant (T4-2) breast cells in which glucose metabolism is inhibited by the addition of 2-deoxy-D-glucose (2DG). Supressing glucose uptake leads to a phenotypic reversion of malignant cells (they look normal) but does not affect non-malignant cells.

AEROBIC glycolysis, glucose metabolism in the presence of oxygen, is not the consequence of the cancerous activity of malignant cells, as it was believed to be, but is itself a cancerous event. This was demonstrated by scientists of the University of California, Berkeley, and Hokkaido University, Japan.

“A dramatic increase in sugar uptake could be a cause of oncogenesis,” says Mina Bissell, an expert on breast cancer and the leading author of the work. “Furthermore… we have discovered two new pathways through which increased uptake of glucose could itself activate other oncogenic pathways. This discovery provides possible new targets for diagnosis and therapeutics.” The researchers examined the expression of glucose transporter proteins in human breast cells. The focus was on the glucose transporter known as GLUT3, whose concentrations were found to be 400 times greater in malignant than in non-malignant breast cells. The results of this study were published in The Journal of Clinical Investigation.

“We found that overexpression of GLUT3 in non-malignant human breast cells activated known oncogenic signalling pathways and led to the loss of tissue polarity and the onset of cancerous growth,” Mina Bissell said. Conversely, it was found that when GLUT3 was reduced in malignant cells they behaved as if they were non-malignant even though they still contained the malignant genome.

In 1924, the biochemist and future Nobel laureate Otto Heinrich Warburg hypothesised that increased aerobic glycolysis at the cost of respiration and higher adenosine triphosphate (ATP) production was a cause and not a symptom of cancer. This hypothesis, however, became controversial because many researchers found aerobic glycolysis in normal cells.

Even now the majority of researchers hold that increased sugar uptake in cells is the result of the greater metabolic demands of tumour cells and not a cause of malignant transformation. In her earlier studies, Mina Bissel found that while Warburg was correct in saying that cancer cells always had increased aerobic glycolysis he was not quite correct in saying that the defect was present in respiratory pathways. She had also discovered that the cause of increased aerobic glycolysis was a dramatic increase in glucose uptake by cancer cells but at that time did not determine whether this increase was the cause of malignant transformation.

The researchers believe their findings help explain why hyperglycemia in diseases such as obesity and diabetes can raise the risk of breast and other cancers. In addition, these results may also help explain why anti-diabetic drugs, such as metformin, which lower blood glucose levels, have been linked to lower cancer risks and mortality.