Folate is a vital water-soluble B vitamin found in a variety of foods, including leafy green vegetables and dry beans. Folic acid is a synthetic form of folate found in supplements and fortified foods. U.S. food manufacturers are required to add folic acid to white flour, enriched pasta, and cornmeal. This is to ensure that pregnant women receive enough of this vitamin to reduce the risk of neural tube defects in their babies. Folic acid is also found in multivitamins. Folate has important roles in DNA synthesis and repair. Folate deficiency is thought to contribute to increased risk of cancer through increased DNA strand breaks, impaired DNA repair, and increased mutagenesis. Dietary folate intake is associated with reduced risk of breast cancer recurrence, especially among women with estrogen receptor negative (ER-) tumors.
However, folic acid has been shown to reduce the expression of beneficial tumor suppressor genes and increase expression of HER2 in breast cancer cells. Folic acid supplementation has also been suspected of promoting the progression of existing breast tumors in some women. Now a new study has demonstrated how folic acid can increase the growth of existing tumors.
Differences in response to folate may have genetic basis
Population studies have reported inconsistent results with respect to folate and breast cancer. These contradictory results suggest that different subgroups may experience varying outcomes from folic acid supplementation, and, given folate's role in DNA synthesis and repair, that these differences may have a genetic basis. There is some evidence for this.
A Swedish study which examined plasma folate concentration in relation to genotypes of a folate-metabolizing enzyme found a genetic variant that was associated with high circulating folate levels. This variant was also associated with increased breast cancer risk. In women with other genotypes, no significant associations between breast cancer and folate levels were observed. A Singapore Chinese study which examined the relationship between green tea (which reduces folate absorption) and risk of breast cancer found that the effect of folate consumption varied based on whether the women possessed certain genotypes.
Latest research shows how folic acid promotes existing tumor growth
The study referenced above was designed to investigate the effects of a high folic acid diet on tumor progression in a mouse model of breast cancer. To conduct the study, the authors fed MMTV-polyoma virus middle T (MMTV-PyMT) transgenic mice (which spontaneously develop mammary tumors) either a high folic acid diet (high folic acid group) or a normal diet (control group) during the period of initial tumor progression. PyMT-induced breast tumors were found to highly express the cancer-specific folate receptor (FRα). Approximately 20% of breast tumors overexpress FRα, which appears to participate in the transformation of breast cancer into aggressive subtypes—FRα is most frequently expressed in triple negative (ER-/PR-/HER2-) and progesterone receptor negative (PR-) breast cancers.
Mice in the high folic acid group developed significantly greater tumor volume than the control mice. STAT3 was activated in the largest tumors (which were found only in high folic acid mice). Downstream signaling via STAT3 promotes human breast cancer growth and progression. Further experimentation showed that STAT3 was activated upon treatment of primary tumor cells harvested from the mice with folic acid. The authors conclude that the results provide a new explanation for folic acid-induced growth of existing tumors.