A recent prospective cohort study undertaken in Melbourne, Australia by Baglietto et al. (2005) concludes that an adequate dietary intake of folate might protect against the increased risk of breast cancer associated with alcohol consumption. Compared with lifetime abstainers, the hazard ratio (risk) for breast cancer in women who regularly consumed an average of 40 g or more of alcohol per day at baseline was observed to be 1.41 and when women also consumed 200 ìg of folate per day the hazard ratio was 2.00 but was 0.77 when women also consumed 400 ìg of folate per day.
1. A role for folate in breast cancer
Folate is involved in the synthesis, repair, and methylation (functioning) of DNA, our genetic map. A deficiency of folate may result in damage to DNA that may lead to cancer (Mulinare et al. 1988), through interference with DNA synthesis and through depletion of labile methyl groups used in biological methylation reactions. Indeed, folate, as 5- methyltetrahydrofolate, has a key role in methyl metabolism. It supplies a methyl group to convert homocysteine to methionine, that is then converted to S-adenosylmethionine, which is the common methyl donor used in biological methylation reactions. For example, DNA hypomethylation or the reduced methylation of DNA due to folate deficiency can contribute to the loss of the normal control or regulation of proto-oncogene expression (Hoffman 1984). A protooncogene is a protein whose normal cellular gene can be converted into a cancer-promoting oncogene by mutation that has abnormal activity and/or is expressed at abnormal levels. This leads to cell death or gives rise to cancer. Folate deficiency has also been associated with single and double DNA strand breaks. Several studies have associated diets low in folate with increased risk of breast, pancreatic, and colon cancer (Gloria et al. 1997, Duthie et al. 2000, Hussien et al. 2005). Conversely, an adequate consumption of folate may reduce the risk of breast cancer (Shrubsole et al. 2001), and research results from a study of over 121,000 nurses suggests that long-term folic acid supplementation (for 15 years) is associated with a decreased risk of colon cancer in women 55 to 69 years of age (Christensen 1996). Indeed, in animal models, folate supplementation reduces DNA strand breaks in the p53 gene (Kim et al. 2000); the P53 protein regulates the cell cycle to prevent genome mutation, and hence functions to suppress tumors. It can activate DNA repair proteins when it recognizes damaged DNA, hold the cell cycle at the G1/S regulation point on DNA damage recognition to prevent uncontrolled cell division and can initiate apoptosis, the programmed cell death, if the DNA damage proves to be irreparable.
Cancer occurs when the rate of proliferation of mutated cells greatly exceeds the rate of apotosis. In breast cancer, the gene has been observed to be mutated in 15 to 50% of tumors (Olivier and Hainaut 2001). Furthermore, when tumor receptor status for estrogen is considered, folate deficiency may be associated primarily with estrogen receptor negative (ER-) breast cancer tumours (Zhu and Williams 1998, Zhang et al. 2005).
2. A role for alcohol in breast cancer
Alcohol was first identified as a risk factor for breast cancer in 1977, and the international data has been relatively consistent that there is a dose-response effect. From pooled analysis of data, the relative risk increase by 1.09 for each 10 g alcohol (equivalent to one standard drink) consumed per day up to 60 g, such that consumption above 60 g per day is not associated with a further increased risk (Smith-Warner et al. 1998). The association between alcohol consumption and breast cancer is not modified by other risk factors, and the consumption of alcohol appears additive to other risk factors. The underlying mechanisms have not been conclusively established but may include the influence of alcohol on the circulating concentration of estrogens such that an elevated concentration of estradiol increases the risk of breast cancer approximately five-fold (Dorgan 1994), and from human breast cancer cell lines, alcohol is observed to selectively stimulate positive estrogen receptors (ER+).
There is accumulating data that the primary metabolite of alcohol, acetaldehyde, is predominantly responsible for alcohol-associated carcinogenesis. Acetaldehyde is directly carcinogenic and mutagenic interfering with both DNA synthesis and repair. It also binds to cellular proteins and DNA forming stable protein and DNA adducts, which result in physical and functional impairment of the cell and consequently in an immunological cascade reaction, and in the occurrence of replication errors and/or mutations in oncogenes or tumor suppressor genes (Dellarco 1988, Fang and Vaca 1995, Nakamura et al. 2003). Acetaldehyde also degrades folate in the colon.
Other mechanisms by which alcohol may induce carcinogenesis include the induction of cytochrome P-4502E1, which is associated with an increased production of reactive oxygen species that are associated with DNA damage including single and double strand breakage (Wright et al. 1999, Koch et al. 2004), where breast tissue tumors contain an approximate nine-fold higher concentration of these DNA modifications (Li et al. 1999).
Induction of cytochrome P-4502E1 by alcohol is also associated with an increased activation of certain dietary and environmental carcinogens. Alcohol may additionally influence alterations in cell cycle behaviour such as cell cycle duration leading to the hyperproliferation of mutated cells, that is, uncontrolled cell division; nutritional deficiencies, such as methyl-, vitamin E-, folate-, pyridoxal phosphate-, zinc- and selenium deficiencies; and alterations of the immune system eventually resulting in an increased susceptibility to certain virus infections such as hepatitis B virus and hepatitis C virus (Poschl and Seitz 2004).
3. Effect of alcohol consumption on folate bioavailability. The effects of folate deficiency are aggravated by an excessive or high consumption of alcohol (Su and Arab 2001), probably because acetaldehyde, the primary metabolite of alcohol, degrades folate in the colon (Homann et al. 2000). For example, when acetaldehyde is subsequently oxidised by xanthine oxidase to acetate, the reactive oxygen species generated cleave folate into biochemically inactive metabolites (Shaw et al. 1989). Indeed, folate deficiency is a common clinical sign of chronic alcohol consumption (Wu et al. 1975). High alcohol consumption has also been observed to reduce the intestinal absorption and hence bioavailability of folate (Halsted et al. 1971) as well as reduce the renal tubular reabsorption of folate thus increasing its urinary excretion (Russell et al. 1983). Consequently, high consumption of alcohol when combined with inadequate consumption of folate has been observed to increase the risk of colorectal adenomas and carcinomas (Giovannucci et al. 1995, Boutron- Ruault et al. 1996) and breast cancer in postmenopausal women (Sellers et al. 2001).
4. Potential interaction between alcohol and folate in breast cancer. Diet and lifestyle, type of breast tumour, stage of disease and genetic polymorphism have, however, been identified as potential modifiers of alcohol’s risk. Studies by Zhang et al. (1999, 2005), Rohan et al. (2000) and Sellers et al. (2001), all suggest that adequate folate consumption may protect against the increased risk of breast cancer associated with alcohol consumption. For example, folate is involved in DNA synthesis and methylation influencing gene expression, while alcohol is a folate antagonist, interfering with DNA synthesis and repair. The concurrent use of alcohol and folate (at least 300 mg/day) has been observed to reduce the relative risk of alcohol-induced breast cancer to 1.05 for women consuming greater than 15 g alcohol/ day or one and a half standard drinks, but was only 0.55 for women consuming greater than 600 mg/day of folate. Indeed, the concurrent use of folate-containing vitamin supplements reduces the relative risk to 0.74 for women consuming greater than 15 g alcohol/day compared to those not using vitamins (Zhang et al. 1999). One recent study has considered tumor receptor status for estrogen when researching the interaction between alcohol and folate. The interaction has been observed to be primarily limited to estrogen receptor negative (ER-) breast cancer tumors (Sellers et al. 2002), which is consistent with an interaction of alcohol and folate on breast tissue tumors being mainly through the primary metabolite of alcohol, acetaldehyde, which is directly carcinogenic as well as indirectly carcinogenic via folate depletion, independent of circulating estrogens and estrogen receptor mediated events.
In conclusion, there is emerging epidemiological evidence, which is supported by in vitro and in vivo evidence, that supplementation of the diet with folate while consuming excessive or high amounts of alcohol may reduce the risk of breast cancer (Tjonneland et al. 2005).
This information has important public health implications given that approximately 8.5% of Australian
women consumers aged from 18 years of age, for example, reportedly regularly consume alcohol in excess (National Health Survey 2001), and it has been proposed that at approximately 4% of breast cancers in developed countries are attributable to alcohol (Collaborative Group on Hormonal Factors in Breast Cancer 2002). Furthermore, it has been suggested that supplemental folic acid in foodstuffs such as bread, might negate the anti-folate effects of alcohol, which increases the risk of breast cancer; indeed supplementation of bread flour with thiamine in Australia has significantly reduced the risk of Wernicke Korsakoff syndrome in alcohol dependent consumers (Harper et al. 1998).
Creina Stockley is Health and Regulatory Information Manager at The Australian Wine Research Institute and a member of the AIM Council
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