A new review reveals how folic acid can act as both a friend and foe in breast cancer, protecting at moderate doses, but potentially fueling tumor growth when intake is excessive or genes go awry.
Review: The Role of Folic Acid in DNA Methylation and Breast Cancer. Image Credit: Prostock-studio / Shutterstock
A review article published in the International Journal for Vitamin and Nutrition Research describes the involvement of folic acid in DNA methylation and breast cancer progression.
Background
Folic acid is a synthetic form of vitamin B9 commonly found in dietary supplements and fortified foods. Synthetic folic acid is actually more bioavailable than naturally occurring food folate, but problems can arise primarily from deficiency, malabsorption, or certain genetic variants. It plays a pivotal role in the biosynthesis of nucleotides, amino acids, and neurotransmitters. Deficiency of folic acid, rather than low bioavailability of the synthetic form, disrupts DNA repair and methylation processes, contributing to carcinogenesis.
Folic acid deficiency has been linked to various cancer types, including prostate, gastric, liver, lung, brain, blood, and breast cancers. This review article particularly focused on breast cancer, as it is the most common cancer and a leading cause of mortality in women. Cancer is a multifactorial disease triggered by a complex interplay between genetic, epigenetic, and environmental factors. DNA methylation is an epigenetic factor that affects gene expression by preventing the binding of transcription factors to DNA.
Folic acid deficiency is associated with global DNA hypomethylation, which can potentially lead to increased expression of proto-oncogenes. Folic acid deficiency can also be associated with DNA hypermethylation in specific gene regions, resulting in the transcriptional inhibition of tumor suppressor genes. These changes in DNA methylation patterns due to folic acid deficiency can potentially increase the risk of cancer. The review highlights that both hypomethylation and hypermethylation can occur depending on the context, and these methylation changes may affect genes important for tumor suppression or oncogene activation, such as BRCA1 and HER2.
Folic acid in breast cancer
Studies investigating the effect of folic acid on breast cancer risk have produced mixed results. Animal studies have shown that moderate folic acid deficiency significantly inhibits breast cancer progression and that folic acid supplementation has no apparent effect on breast carcinogenesis. Importantly, the timing and dose of folic acid intervention appear to be crucial factors influencing these effects.
Tumor-promoting effects of folic acid have also been observed in animals supplemented with folic acid at 2.5 and 5 times the recommended daily allowance (RDA). Folic acid-induced increased expression of human epidermal growth factor receptor 2 (HER2) might be associated with breast cancer progression.
Folic acid has been found to induce caspase-dependent cell death (apoptosis) in human breast cancer cells. As the researchers propose, folic acid influences the level of a key methyl donor, leading to alterations in DNA methylation and gene expression. However, the review also notes that high concentrations of folic acid can increase methylation of tumor suppressor genes, potentially facilitating cancer progression in some cases.
These observations collectively suggest that folic acid at lower concentrations may prevent cancer progression, whereas at higher concentrations, it may promote cancer progression by downregulating the expression of key tumor suppressor genes.
Evidence gathered from human cancer cell line studies suggests that folic acid-induced alterations in gene expression are specific to the type of cancer. In some breast cancer cells, folic acid has been found to promote migration, proliferation, and vascularization, while also suppressing apoptosis and cell differentiation. These findings suggest that folic acid treatment can lead to the development of more aggressive cancer phenotypes. The review emphasizes that these effects are cell line-specific and may depend on the expression of folate transporters and other molecular features.
Genetic variants in the folic acid metabolic pathway
Genetic variants in the folic acid metabolic pathway genes, including MTHFR and RFC, have been found to increase the risk of breast cancer by reducing the bioavailability of folic acid and impairing its functions. The MTHFR gene is associated with folic acid utilization, and the RFC gene is associated with folic acid transportation in the body.
The two identified variants of the MTHFR gene (C677T and A1298C) have been found to associate with reduced activity of the MTHFR-encoded enzyme, leading to altered folic acid metabolism and DNA hypomethylation. The association between these gene variants and breast cancer risk may be stronger in some populations, such as Asian women, and the risk appears to be higher when both low enzyme activity and low dietary folate intake are present.
The G80A variant of the RFC gene has been found to be associated with the downregulation of folic acid transportation, which leads to folic acid deficiency.
The overexpression of folate receptors (FR α and β) has also been observed in breast cancer, which is associated with an induction in folic acid uptake and promotion of tumor cell growth.
Folic acid deficiency has been found to cause a DNA base substitution in the DNA repair process that the repair mechanisms may not effectively identify, which in turn may contribute to DNA strand breaks.
Folic acid for breast cancer treatment
Folic acid supplementation has been linked to a reduced risk of breast cancer. However, the review emphasizes that both excessive and deficient folic acid intake can be detrimental, and maintaining an optimal intake is crucial. Preclinical trials have demonstrated that nanoparticles targeting folate receptors can effectively inhibit the growth of breast cancer cells in mice without causing significant side effects. These nanoparticle-based strategies are experimental and represent a future direction for research rather than established therapies.
In human clinical trials, consumption of 153 to 400 micrograms of folic acid has been found to reduce breast cancer risk in women. However, both preclinical and clinical findings indicate that excessive consumption of folic acid can increase the risk of cancer if preneoplastic lesions are present. The review notes that intake above 400 micrograms per day does not confer further risk reduction and may even increase risk in certain contexts.
A case-control study involving Mexican women with breast cancer has found an inverse association between folic acid intake and cancer risk. The study has found a greater protection against breast cancer in postmenopausal women, and a higher risk in women who consumed low concentrations of folic acid.
Overall, studies investigating the relationship between folic acid and breast cancer highlight the need for more researchers to refine folic acid intake recommendations and explore its therapeutic efficacy in cancer. The review also notes that most current evidence originates from animal and in vitro studies, which may not directly translate to human populations, and that contradictory findings make it challenging to establish clear recommendations for folic acid supplementation in breast cancer patients. Further research, including retrospective human studies, is needed to clarify the dose-response relationship and the influence of genetic and lifestyle factors.