Abstract
Cancer cell metabolism differs from non-transformed cells in that cancer cells do not employ oxidative phosphorylation for ATP-production from glucose even in the presence of adequate oxygen concentrations. This conjecture increases the cancer cell's reliance on glucose, potentially reducing the cancer cell's ability to utilize non-glucose substrates. The main alternative to glucose are high-energy breakdown products of hepatic lipid metabolism, collectively termed ketone bodies. Non-transformed cells are able to metabolize ketone bodies to form ATP, but the role of ketone bodies’ metabolism in human breast cancer cells is unclear, since it relies on metabolic functions downstream of glucose metabolism. Here we aimed to determine if human breast cancer cells will utilize ketone bodies (beta-hydroxybuterate) as energy substrate in the absence of glucose.
Cell proliferation of MDA-MB-231 and MCF-7 human breast cancer cells was measured after 48 h or 72 h of treatment using an MTT-Assay. Treatment conditions were various glucose concentrations (4.5 g/l to 0 g/l) and 25 nM beta-hydroxybuterate (BHB) for all cells after overnight serum starvation.
After 48 h, cell proliferation decreased to 47% (p<0.001) in no glucose medium compared to proliferation observed for cells in 4.5 g/l glucose for MDA-MB-231 cells. Cell proliferation at glucose concentrations as low as 0.125 g/l did not change cell proliferation in these cells. After 48 h, cell proliferation of MCF-7 cells decreased to 24% (p<0.001) for cells treated with 0 g/l glucose, to 83% (p = 0.0078) for cells treated with 0.125 g/l glucose and to 87% (p = 0.0108) for cells treated with 0.25 g/l glucose.
After 72 h, cell proliferation decreased to 30.5% (p<0.001) after treatment with no glucose compared to proliferation observed for cells in 4.5 g/l glucose for MDA-MB-231 cells. Cell proliferation at glucose concentrations as low as 0.125 g/l did not significantly change cell proliferation in these cells. After 72 h, cell proliferation of MCF-7 cells decreased to 22% (p<0.001) for cells treated with 0 g/l glucose and to 74% (p = 0.0288) for cells treated with 0.125 g/l glucose compared to proliferation observed for cells in 4.5 g/l glucose. All conditions and time points had been supplemented with 25 nM BHB.
These preliminary results indicate that human breast cancer cells are not able to use ketone bodies as energy substrates in the absence of glucose. An additional finding was also that more aggressive, triple-negative breast cancer cells are able to survive with very low glucose conditions. Pending further investigation, this may provide a rationale for dietary carbohydrate restriction as neoadjuvant therapy for breast cancer patients, but may necessitate further glucose restrictions than what can be achieved through diet alone.
Citation Format: Alyssa M. Dixon, Michael Weichhaus. Breast cancer metabolism: Are ketone bodies energetic substrates. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 35.
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