It is generally known that folate (vitamin B9) is important in early pregnancy to prevent neural tube defects in babies, because folate is needed by rapidly dividing cells (e.g., those of a developing embryo) for DNA synthesis and cellular energy production. As a consequence, many processed foods in the United States are fortified with folate. Aggressive cancers are also defined in part by their rapidly dividing cells, and antifolate drugs such as methotrexate that block activation of folates are first-line chemotherapeutics. Whether the fortified folate levels in our foods could contribute to cancer progression is unclear, as existing studies of the effects of low-folate diets on cancer have produced conflicting results. In a recent article in Molecular Cancer Research, NRI scientists report results of folate restriction on several breast cancer subtypes.

What they did:
In “Metabolic reprogramming by folate restriction leads to a less aggressive cancer phenotype,” NRI faculty Sergey Krupenko, PhD, and Stephen Hursting, PhD, MPH, sought to clarify the folate-cancer connection through a detailed analysis of the effects of folate restriction on the metabolic properties of three breast cancer cell lines. The three cancer subtypes included one that was non-invasive, one that was invasive but minimally metastatic, and one that was highly metastatic. Krupenko and Hursting were joined in this research by Mirko Hennig, PhD, an NRI Visiting Scholar, and Xiuxia Du, PhD, a faculty member of UNC Charlotte who is based at the North Carolina Research Campus. They compared cell properties including proliferation, migration, and invasion, and also looked at cellular levels of specific metabolites in order to understand molecular changes within the cells that were caused by folate-restricted feeding.

The results show that folate restriction causes changes in certain metabolite levels and the expression of specific genes. Folate restriction also causes change in cellular energy metabolism, and decreases cells’ invasiveness. Overall, folate restriction shifted cancer cells toward less aggressive phenotypes. The magnitudes of observed changes were dependent on cell line, with the invasive/non-metastatic subtype showing the most effects.

What it means:
Results to date regarding the utility of low-folate diets in treatment of breast cancer are conflicting. This study shows that folate restriction does alter the properties of cancer cells, but that specific cellular changes, and implicitly, benefits of treatment, are dependent on the cancer subtype. The decision to target the folate pathway, either through dietary or pharmaceutic means, will depend on the nature of an individual’s cancer.

Ashkavand Z, O’Flanagan C, Hennig M1, Du X2, Hursting SD, Krupenko SA (2016). “Metabolic reprogramming by folate restriction leads to a less aggressive cancer phenotype.” Mol Cancer Res. In press.
1UNC-NRI Visiting Scholar