Folate, DNA Methylation and Breast Cancer Metastasis
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Folate is a B vitamin that is essential for making DNA and controlling gene expression. Both normal cells and cancer cells need folate for these purposes. In 1998, the United States Government mandated cereal and grain fortification with folic acid (the supplement form of folate) to reduce the number of birth defects. The folic acid fortification program has been successful in this regard, but now the general population is receiving more folic acid in the diet than ever before. Of concern is that excess folic acid intake will cause cancers to grow or metastasize more quickly than they would at lower levels of intake.
 
 
 
 
 
 
 
 DNA undergoes a chemical modification, called methylation, which regulates the expression of genes. Folate metabolism produces compounds for this reaction. When folate levels are low, gene expression may change. Many cancers, including breast cancer, demonstrate gene expression differences compared to normal cells due to changes in methylation (i.e. hypermethylation). In addition, metastases show differences in gene expression compared to the primary breast tumor. If a cancer cell is dependent on a particular DNA methylation pattern to maintain its “cancerness” or metastatic potential, then manipulation of folic acid intake may impact the progression of cancer.
 
 
 
 
 
 
 
 Our research project hypotheses are: 1) folate deficiency and the DNA-demethylating agent, 5-aza-deoxycytidine, will decrease incidence of metastasis; 2) excess dietary folate will increase incidence of metastasis; 3) folate deficiency and 5-aza-deoxycytidine will increase the expression of specific genes that are typically repressed in tumors; and 4) differences in gene expression in primary and metastatic tumor cells exposed to different levels of dietary folate and 5-aza-deoxycytidine will affect methylation status of specific genes. We will utilize a special mouse model (transplantable murine mammary intraepithelial neoplasia outgrowths or MIN-Os), which is a highly predictable system in terms of the time from transplantation to incidence of local tumor to incidence of metastasis. After breast tumor transplantation, the mice will be fed a diet that varies in folic acid compared to regular chow (the control diet). Some mice will receive weekly injections of 5-aza-deoxycytidine. We will use PET (positron emission tomography) scans to detect non-invasively tumor metastasis in the mice. Incidence of metastasis, microscopic tissue morphology (pathology), and analysis of gene expression differences on tumor samples will be compared among the treatment groups. We will compare tumor gene expression patterns in folate-deficient and 5-aza-deoxycytidine-treated mice with control and folate-excess mice. We will then investigate DNA sequences to determine gene-specific methylation status.
 
 
 
 
 
 
 
 Currently, there are no effective treatments for breast cancer metastasis. The data from this project will potentially define how dietary intake of folic acid affects breast tumor metastasis.