Breast cancer is a common malignancy in females and is a leading cause of deaths among women globally. There are several risk factors that contribute to the pathogenesis of breast cancer including family history, nutrition, age, as well as epigenetic changes (Agrawal et al. 2007). Genetic mutations often underlie both the development and progression of breast cancers, however epigenetic mechanisms have recently been classified as a significant factor contributing to the development of breast cancers. The most extensively studied epigenetic mechanism is the covalent addition of a methyl group, DNA methylation. DNA methylation is believed to occur early in the development of breast cancer which consequently activates oncogenes and silences tumour suppressors leading to proliferation of abnormal cells (Agrawal et al. 2007).
In the case of gene expression being altered by DNA methylation, it is usually categorised as being either due to hypomethylation or hypermethylation. In general, cancer cells usually display extensive hypomethylation of genomic DNA as well as hypermethylation at promoter regions that are generally unmethylated (Vo and Millis 2012; Zhang et al. 2012). Global hypomethylation, defined as the degree of methyl attachment to cytosine residues of DNA sequences throughout the genome, may be associated with breast cancer risk (Agrawal et al. 2007; Choi et al. 2009). Thus global hypomethylation especially in peripheral blood DNA has become an independent risk factor for many cancers including breast cancer (Choi et al. 2009; Wu et al. 2012a; Wu et al. 2011).
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Despite global hypomethylation being an independent risk factor, few studies have assessed the association between DNA methylation in white blood cells (WBC) and breast cancer risk (Brennan et al. 2012). Previous breast cancer studies have shown significant correlations in methylation levels between tumour tissue and white blood cell (WBC) DNA using repetitive elements Sat2, LINE-1,and Alu (Cho et al. 2010; Wu et al. 2012b). The observed decreased methylation in blood collected prior to cancer diagnosis is evident in some repetitive elements including Alu or LINE-1, indicating the probable association between global hypomethylation and cancer risks (Wu et al. 2012a). Epidemiological studies suggest that additional factors such as nutrition may also change methylation levels in WBC DNA (Wu et al. 2011).
Breast cancer, DNA Methylation and Folate
There is a great deal of interest in assessing how changes in nutritional factors modulate DNA methylation in order to link it to disorders and chronic diseases such as cancer (Crider et al. 2012). Folate, a water soluble B vitamin, is present in particularly high concentrations in green leafy vegetables and citrus fruits. In its synthetic form it is known as folic acid which is evident in some fortified foods. Folate has the ability to maintain genomic stability by regulating biosynthesis of DNA, DNA repair as well as DNA methylation (Duthie 2011; Gonda et al. 2012).
The primary methyl donor for DNA methylation, S-adenosylmethionine (SAM), is produced in one-carbon metabolism. Folate is required in one-carbon metabolism and functions in converting homocysteine into methionine and thereafter into SAM (Figure 1). In one-carbon metabolism a reduction of folate decreases SAM, and increases S-adenosylhomocysteine (SAH) which inhibits methyltransferases (Kim et al. 2009). Thus when low-dietary folate is evident, SAM concentrations are low, causing global DNA hypomethylation and consequently increases proto-oncogene expression (Figure 1).
Figure 1. A simplified diagram describing the manner in which folate deficiency may alter normal DNA methylation and how this potentially affects the risk of cancer (Adapted from Duthie 2011)
Despite the important function of folate in the one-carbon metabolism, the role of dietary folate in cancer is a controversial topic (Lu et al. 2011). Mammals are unable to synthesise folate de novo and therefore obtain folate from either natural foods, supplemented foods or from microbial breakdown during digestion. Folate status can be measured in two ways: 1) dietary folate intake or 2) blood and/or tissue folate levels. Individuals with low blood folate concentrations or low levels of dietary folate are more likely to have a significantly increased chance of developing several cancers (Duthie 2011).
Low-folate status has been associated with the development of cervix, lung, breast, brain, colon and pancreas cancers. The evidence that links folate deficiency to human cancer is strongest for colon cancer (Duthie 2011). However, recently there has also been an increase in interest in studying the relationship between folate status and breast cancer risk (Kotsopoulos et al. 2012). It has become apparent that there may be a negative association between dietary folate and the risk of breast cancer (Lu et al. 2011). However case-control studies and prospective studies are inconsistent with regard to folate and breast cancer risk.
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Despite a negative association found in some studies, no significant association between folate intake and risk of breast cancer has been found in other studies (Aune et al. 2011). Case-control studies have provided evidence that low folate intake may be associated with increased risk for breast cancer (Aune et al. 2011). Alternatively, high folate intake may instead increase breast cancer risk. The effect of high folate intake and an increase in breast cancer development is important with regard to individuals predisposed to developing cancer, such as having a strong family history of breast cancer (Kotsopoulos et al. 2012). Nonetheless, it is still suggested to ensure adequate folate intake in order to decrease the possible risk for breast cancers (Vo and Millis 2012).
It is possible for folate deficiency to result in global DNA hypomethylation in both human and animal cell lines in vitro (Duthie 2011). Interestingly, the effect of supplementation with synthetic folic acid to increase global DNA hypomethylation is inconsistent as it depends on a number of factors including initial folate status, the level and duration of intervention, the genes and tissue involved as well as the health of an individual (Duthie 2011). There is however a chance that folic acid supplementation may increase global DNA methylation thereby enabling protection against DNA damage, ultimately reducing the risk of tumour transformation (Gonda et al. 2012). Moreover, other breast cancer risk factors besides nutritional factors such as aging also alter DNA methylation.
Breast cancer, DNA methylation, Folate and Aging
Aging includes an increase of both genetic and epigenetic alterations in the genome, which have the potential to alter the expression of genes related to carcinogenesis. There is a great deal of interest determining whether the process of aging influences folate metabolism in cancers and if it is possible for folate supplementation to prevent the procarcinogenic effects associated with aging. With aging, changes in cellular biology may occur and may subsequently reduce folate availability in certain tissues and disturb one-carbon metabolism, resulting in both the impairment of nucleotide synthesis and biological DNA methylation (Figure 2) (Jang et al. 2005).
The process of aging increases homocysteine, a sulfur containing amino acid formed in folate-mediated one-carbon metabolism (Kim et al. 2009). With aging, folate status tends to decline due to both decreased folate intake as well as altered folate availability, thus folate depletion can result in DNA hypomethylation in elderly women (Kim et al. 2009). Given that aging alone affects DNA methylation, a potential synergistic effect between folate status and aging on DNA methylation has been investigated with regard to cancer development; however the focus has mainly been in colon cancer.
Normal ageing is however also linked to altered DNA methylation patterns, therefore determining the effects of diet alone on DNA methylation and disease risk is complex (Duthie 2011). It has been previously suggested that as an individual ages, cancer development is enhanced by 1) a reduction of genomic DNA methylation or 2) an increase of promoter methylation of tumour suppressor genes (Jang et al. 2005; Sauer et al. 2010; Wu et al. 2011). In general, genome-wide DNA methylation seems to decrease during the aging process (Jang et al. 2005; Kim et al. 2009). This age-related decrease in global DNA methylation mainly occurs in repeated sequences (Ford et al. 2011). There is however substantial inter-individual differences in how global DNA methylation varies over time (Ford et al. 2011). The response of DNA methylation to ageing is also tissue-specific and can be contradicting for many cancers (Jang et al. 2005; Kim et al. 2009).
Figure 2. Proposed diagram showing candidate mechanisms for interactions between folate, aging and DNA methylation in carcinogenesis (Adapted from Jang 2005 and Kim et al. 2009)
Genomic DNA hypomethylation, common during aging, is observed in various malignant tissues, however the role of age-associated genomic hypomethylation in carcinogenesis is not yet fully known (Kim et al. 2009). There is uncertainty about whether inhibition of hypomethylation or hypermethylation can inhibit carcinogenesis (Agrawal et al. 2007). In addition to risk factors such as folate intake and aging, hypomethylation has previously been suggested to be a stronger risk factor for women with a family history of breast cancer (Choi et al. 2009). The effect of age and folate status on DNA methylation has been of main focus in colon cancer and has not been proposed in breast cancer yet (Keyes et al. 2007; Sauer et al. 2010). Studies regarding this subject have also mainly been studied in animals such as mice (Keyes et al. 2007; Sauer et al. 2010). Ly et al. (2012) proposed the investigation of the interaction between folate and aging on genomic and gene-specific DNA methylation and susceptibly to a particular disease.
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