If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Address correspondence to: Isabelle Romieu, MD, MPH, ScD, Head, Section of Nutrition and Metabolism, International Agency for Research on Cancer, 150 Cours Albert-Thomas, 69372 Cedex 08, France
Consumption of alcoholic beverages is one of the single most important known and modifiable risk factor for human cancer. Among women, breast cancer is the most common cancer worldwide and the leading cause of cancer-related mortality. Consumption of alcoholic beverages is causally associated with female breast cancer and the association shows a linear dose–response relationship. The role of heavy drinking has been long recognized and even a moderate intake is associated with an increased risk for breast cancer. The present review is an update of the current evidence on the association between alcohol consumption and breast cancer risk. The aim is to gain further insight into this association and to improve our current understanding of the effects of the major modifying factors.
Evidence acquisition
Epidemiologic and experimental studies published since the most recent International Agency for Research on Cancer (IARC) Monograph on alcoholic beverages were identified in PubMed using a combination of keywords such as alcohol, breast cancer, polymorphisms, menopausal status.
Evidence synthesis
Cumulative lifetime consumption, drinking frequency, drinking patterns and timing of exposure each modulate the association between alcohol consumption and breast cancer. Hormonal status, genetic polymorphisms, and nutritional factors may interact with ethanol metabolism and further influence breast cancer risk.
Conclusions
Better standardization among experimental and epidemiologic designs in assessing alcohol intake and timing of exposure may improve our understanding of the heterogeneity observed across studies, possibly allowing the quantification of the effects of occasional heavy drinking and the identification of a window of higher susceptibility to breast cancer development.
Introduction
Consumption of alcoholic beverages has been linked to a large number of health impairments, chronic diseases, and death worldwide.
In 1988, the International Agency for Research on Cancer (IARC) established the carcinogenicity of alcoholic beverages, based on an increased risk of liver cancer among alcoholics and populations with high-level intakes.
Alcohol consumption causes cancers of the oral cavity; pharynx; larynx; esophagus; colorectum; liver (hepatocellular carcinoma); and female breast. In addition, the IARC Working Group concluded that ethanol in alcoholic beverages is carcinogenic to humans (Group 1), and acetaldehyde associated with the consumption of alcoholic beverages is carcinogenic to humans (Group 1).
The role of ethanol metabolism in tumor initiation is implied by the associations observed between different forms of cancer and polymorphisms in genes involved in the oxidation of ethanol. Whether, or to what degree, these associations are explained by redox changes, formation of radicals, effects on intermediary metabolism, and/or effects on other pro-carcinogens cannot be established from current findings. Concerning the relationship between alcohol consumption and breast cancer, the underlying biological mechanisms are not well defined. Estrogens and androgens are well-known activators of cellular proliferation, which is associated with an increased risk of breast carcinogenesis. Alcoholic beverage consumption in women causes an increase in levels of endogenous estrogens, which has been suggested to contribute to the development of breast cancer. Alcohol dehydrogenase (ADH)–mediated alcohol oxidation, which increases the hepatic redox state, which in turn inhibits catabolism of sex steroids, has been suggested as the mechanism for the alcohol-mediated elevation in steroid levels.
Given the high prevalence of moderate alcohol drinking among women in many populations,
Social inequalities in alcohol consumption and alcohol-related problems in the study countries of the EU concerted action “Gender, Culture and Alcohol Problems: a Multi-national Study.”.
alcohol-related breast cancer is an important public health issue. The total percentage of alcohol-attributable breast cancer cases is estimated at 5% (95% CI=2%, 8%) among women in eight European countries.
At present, several aspects of the association of alcohol consumption with breast cancer risk are not fully elucidated. Since the most recent IARC Monograph,
new studies have provided relevant information on issues regarding the types of alcoholic beverages, the timing and pattern of exposure, potential modifying factors, and polymorphisms in genes involved in the mechanisms of alcohol carcinogenesis (exemplified in Figure 1 and summarized in Table 1). In this review, the focus is on the new available data, with background information on the mechanisms of alcohol-related carcinogenesis.
Figure 1Modifying factors involved in alcohol-related breast carcinogenesis. Schematic representation of ethanol metabolism following alcohol intake and of the main factors that may modulate the association with the risk of female breast cancer
ADH, alcohol dehydrogenase; ER, estrogen receptor; MTHFR, methylenetetrahydrofolate reductase; NHS, Nurses’ Health Study; PR, progesterone receptor; WHS, Women’s Health Study
Since that report, new data have become available and have been considered in this analysis. The PubMed/MEDLINE search was restricted to publication dates between November 2009 and January 2013 and to articles published in English. Key words, alone or in combination, included breast cancer, alcohol, binge drinking, menopausal status, ER (estrogen receptor), PR (progesterone receptor), ADH, ALDH (aldehyde dehydrogenase), GSTM1 and GSTT1 (glutathione-S-transferases), BRCA (breast cancer–susceptibility gene), MTHFR (methylenetetrahydrofolate reductase), and folate. References cited by the relevant retrieved articles were also reviewed. In addition, some studies on mechanisms of alcohol-related carcinogenesis were included for background information.
Evidence Synthesis
The causal relationship between consumption of alcoholic beverages and breast cancer risk is supported by epidemiologic studies, and corroborated by animal and in vitro evidence.
Alcohol, tobacco and breast cancer—collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease.
Association of lifestyle and other risk factors with breast cancer according to menopausal status: a case-control study in the Region of Western Pomerania (Poland).
reported a linear dose–response with increasing daily or cumulative intake. For each additional standard drink/day, breast cancer risk is estimated to increase from 2% (relative risk [RR]=1.02, 95% CI=1.01, 1.03) up to 12% (RR=1.12, 95% CI=1.09, 1.14).
The most striking increase in risk is provided by the Million Women Study, which performed an analysis of more than 28,000 incident cases and reported a linear increase in breast cancer risk with increasing alcohol consumption.
Those few studies that reported a nonsignificant or null association included a small number of drinkers compared with nondrinkers, lacked quantitative assessment of alcohol intake, or did not adjust for potential confounders.
Dietary patterns and risk of cancer of various sites in the Norwegian European Prospective Investigation into Cancer and Nutrition cohort: the Norwegian Women and Cancer study.
Dimensions of Alcohol Consumption and Types of Alcoholic Beverage
Dimensions of alcohol consumption
Exposure to alcohol is expressed either in percentage by volume (how many milliliters of alcohol are present for every 100 mL of beverage at 20°C) or in ethanol intake (number of drinks per time-period, typically per day or per week; one drink is equivalent to 10–12 g of pure ethanol). Alcohol percentages by volume are typically 4%–5% for beer, 12% for wine, and 40% for distilled spirits; however, these may vary widely. Ethanol content may range from 3% to more than 10% in beer (home-brewed or locally produced beers, such as sorghum beer, exhibit a lower alcohol content), from 8% to 15% in wine, and from 20% in aperitifs to 80% in some types of absinthe.
Most studies evaluate the average volume of alcoholic beverage intake, possibly leading to bias in assessing exposure, since the size and strength of each drink are unknown.
The lack of a global harmonization in dimensions of alcohol consumption prevents us from drawing firm conclusions about safe levels of alcohol intake.
World Cancer Research Fund/American Institute for Cancer Research Food, nutrition, physical activity and the prevention of cancer: a global perspective.
Overall, the difference in breast cancer risk between different types of alcoholic beverage is not consistent and provides further evidence that ethanol is the main causal factor.
and many compounds present in various alcoholic beverages, such as nitrosamines, may contribute to the development of breast cancer. In contrast, phytochemicals contained in red wine could act as protective factors on breast cancer development.
In experimental settings, these natural phenolic compounds were shown to inhibit the activity of aromatase or to alter DNA methylation after exposure to ethanol.
Further in vivo studies may contribute to elucidating whether chemicals other than ethanol contained in alcoholic beverages increase or decrease the risk of breast cancer among alcohol drinkers.
Age at start of drinking
Consumption of alcoholic beverages as a risk factor for breast cancer may interact with other breast cancer risk factors such as hormonal status or first full-term pregnancy,
A limited number of studies have investigated the presence of a window of higher susceptibility to alcohol-related carcinogenesis. In utero exposure of rats leads to an increased frequency of malignant mammary tumors in offspring.
The Nurses’ Health Study (NHS)–II shows that alcohol consumption during adolescence and early adulthood is dose-dependently associated with an increased risk of proliferative benign breast disease, which may lead to invasive breast cancer later in life.
Similar results are observed at a higher drinking frequency and are consistent with the hypothesis that alcohol carcinogens may preferentially act during mammary development.
ER-positive cells and proliferative activities are at a peak during puberty, and drinking during puberty could trigger a higher risk of breast cancer than that observed for exposure later in life.
However, a detailed prospective analysis of the NHS study and of a large Danish cohort of postmenopausal women could not confirm a difference in risk according to age at start drinking.
Poor information on age at start drinking, recall bias in early lifetime compared with adulthood, and failure to assess alcohol intake throughout the lifetime in some studies, may partially explain the discrepancy between studies. Overall, these findings support the hypothesis that timing of exposure to alcohol carcinogens affects breast tumorigenesis, without however enabling the identification of a window of higher susceptibility. Epidemiologic studies need to provide more comprehensive information on age at start drinking and to precisely assess alcohol intake throughout the lifetime, in light of the important implication in terms of breast cancer prevention.
Occasional heavy drinking
The occasional consumption of ≥60 g of pure alcohol on at least one occasion in the past 7 days
is a drinking pattern known as binge drinking. This type of excessive drinking is increasing particularly among adolescents and young adults of both genders in high-income countries, and creates considerable public health concern and safety problems.
The CDC reported that, in the U.S., about 22% of adolescents engage in binge drinking behavior and that female binge drinkers consume more alcohol overall than other women.
The Nurses’ Health Study reported that female binge drinkers had an increased RR for breast cancer of 1.33 (95% CI=1.11, 1.59) compared with other women.
Binge drinking is a relatively new habit among young women and those few studies exploring such drinking patterns have not yet adopted standardized measure of exposure, thus making comparison of available results difficult. Moreover, reporting bias of actual consumption is likely to be more important in epidemiologic studies on binge drinking, since excessive drinking is more likely to be intentionally underreported by participants.
The leading pathway of ethanol metabolism takes place mainly in the liver where ethanol is oxidized to acetaldehyde, a process catalyzed by ADH and cytochrome P450 2E1 enzymes. Ethanol metabolism may also lead to reactive lipid peroxides, free radicals, and other cytotoxic products, which are detoxified by GSTM1 and GSTT1 enzymes. Acetaldehyde is further converted to the noncarcinogenic acetate by ALDH enzymes. A large portion of ingested ethanol reaches the bloodstream, and may distribute into the breast and be converted to acetaldehyde by ADH enzymes expressed in the breast tissue.
Class I alcohol dehydrogenase is highly expressed in normal human mammary epithelium but not in invasive breast cancer: implications for breast carcinogenesis.
Both ethanol and acetaldehyde interfere with estrogen pathways and may trigger the expression of hormone receptors (e.g., estrogen, prolactin receptors) in breast tumors,
thus modulating the risk according to hormone receptor expression and menopausal status.
Hormone-dependent breast cancer subtypes
Ethanol stimulates both cell proliferation and the transcriptional activity of liganded ER, which in turn increases levels of circulating estrogens that control proliferation and morphogenesis in the breast.
The major clinical breast cancer subtypes, classified according to the presence or absence of hormone receptor expression, are luminal A (ER+ and/or PR+, human epidermal growth factor receptor 2 [Her2] negative), luminal B (ER+ and/or PR+, Her2+), Her2+ (ER–, PR–, Her2+), basal-like or triple negative (ER–, PR–, Her2–), and normal breast-like.
Most studies observe an overall stronger association with ER+ and/or PR+ tumors compared with ER– and/or PR– tumors, for the highest versus the lowest alcohol consumption group.
reported a 12% increase in risk of ER+ tumors for each additional drink, a smaller positive association (7% increase in risk) with all ER– tumors, and no association with ER–/PR– or ER–/PR+ tumors when taken separately. Barnes and colleagues
noted an inverse relationship between alcohol consumption and risk of ER–/PR– tumors. A recent study found a stronger positive association for alcohol-related luminal A or Her2+ overexpressing tumors compared with other subtypes; however, for these rarer subtypes data are still limited.
Nevertheless, the estrogen-dependent pathway cannot solely explain the positive association between alcohol consumption and ER tumors, and the underlying biological mechanisms need further clarification.
Menopausal status
A different association of breast cancer risk with alcohol drinking among pre- and post-menopausal women has been frequently advocated because the large majority of breast cancers, and in particular those occurring after menopause, are hormone-dependent.
Postmenopausal women who use hormone replacement therapy (estrogen plus progestin) show a significant increase in risk of breast cancer (RR=2.24, 95% CI=1.59, 3.14) compared with those who do not, for a daily consumption of at least 20 g of alcohol.
However, despite abundant epidemiologic research, overall the trends in alcohol-related breast cancer risk are similar for pre- and post-menopausal women. For a moderate daily alcohol intake (i.e., 10–20 g), relative risks range from 0.97 (95% CI=0.23, 4.06) to 2.07 (95% CI=1.57, 4.66) in postmenopausal women, versus 0.85 (95% CI=0.31, 2.34) to 1.66 (95% CI=0.90, 3.05) in premenopausal women.
Association of lifestyle and other risk factors with breast cancer according to menopausal status: a case-control study in the Region of Western Pomerania (Poland).
Relationship between potentially modifiable lifestyle factors and risk of second primary contralateral breast cancer among women diagnosed with estrogen receptor-positive invasive breast cancer.
At present, the available evidence does not show that menopausal status alone is a significant modifier of the association between alcohol consumption and breast cancer.
Polymorphisms in Genes Involved in Ethanol Metabolism and Detoxification
Genes regulating alcohol metabolism
Polymorphisms in genes that regulate acetaldehyde formation and detoxification may confer an individual susceptibility to breast cancer by altering the rates of ethanol oxidation and of acetaldehyde elimination in the bloodstream.
In one study in Germany, the ADH1B2 allele showed a protective effect on alcohol-related breast cancer risk.
Interaction of genetic polymorphisms in cytochrome P450 2E1 and glutathione S-transferase M1 to breast cancer in Taiwanese woman without smoking and drinking habits.
Interaction of genetic polymorphisms in cytochrome P450 2E1 and glutathione S-transferase M1 to breast cancer in Taiwanese woman without smoking and drinking habits.
Haplotype patterns in cancer-related genes with long-range linkage disequilibrium: no evidence of association with breast cancer or positive selection.
which leads to low degradation of acetaldehyde, have been reported. The enzyme ADH1C is a member of the ADH family; the 1/1 polymorphic variant induces a 2.5-fold higher rate of ethanol oxidation and confers a 1.8 times higher breast cancer risk compared with wild-type allele, likely due to a prolonged exposure to acetaldehyde.
Breast Cancer Association Consortium Commonly studied single-nucleotide polymorphisms and breast cancer: results from the Breast Cancer Association Consortium.
In addition, recent meta-analyses failed to show an increased risk of breast cancer in ADH1C1/1 allele carriers either in Caucasian or in Chinese populations.
Carriers of GSTM1A and GSTT1-null genotypes fail to detoxify the toxic metabolites of ethanol. Postmenopausal carriers of the GSTT1-null genotype who consume more than 150 g/day of spirit-equivalents showed a substantial increase in risk of breast cancer (OR=3.1, 95% CI=0.6, 15.1) compared with their wild-type counterpart.
One possible explanation for the lack of consistency in results between polymorphisms involved in ethanol metabolism and breast cancer risk is that studies showing a positive association reported on subjects with high regular alcohol consumption.
Folate and MTHFR interaction
Folate (the B-vitamin) is involved in a number of metabolic pathways central to the one-carbon metabolism pathway, DNA synthesis, and cell replication. Folate deficiency leads to misincorporation of uracil, chromosomal instability, and DNA hypomethylation, causing altered gene expression and thus contributing to cancer development.
High prevalence of hyperhomocysteinemia in chronic alcoholism: the importance of the thermolabile form of the enzyme methylenetetrahydrofolate reductase (MTHFR).
In heavy and regular alcohol drinkers, increased degradation of vitamin B, or folate deficiency, are reported, most likely because of a folate-poor diet and to intestinal malabsorption, decreased liver uptake, and increased urinary excretion of folic acid.
The systematic review of the World Cancer Research Fund on nutrition provides further evidence that folate may prevent the carcinogenic action of ethanol in breast tissue.
Is concordance with World Cancer Research Fund/American Institute for Cancer Research guidelines for cancer prevention related to subsequent risk of cancer? Results from the EPIC study.
Folate studies indeed face a multiplicity of challenges, such as inaccurate estimates of folate intake (based on food composition data or self-administered questionnaires instead of serum or whole blood content); recall bias; and confounding (such as healthier behaviors or low alcohol drinking among women with an adequate folate intake).
Most of the genes involved in the one-carbon metabolic pathway are polymorphic in nature and may modulate an individual’s interaction with dietary folate intake. The MTHFR gene is the best studied for cancer susceptibility.
Alcohol consumption and genetic variation in methylenetetrahydrofolate reductase and 5-methyltetrahydrofolate-homocysteine methyltransferase in relation to breast cancer risk.
Cancer Epidemiol Biomarkers Prev.2009; 18: 2453-2459
MTHFR synthesizes the major carbon donor in the remethylation of homocysteine to methionine, and epigenetic deregulation might play a key role in the initiation and progression of breast cancer among drinkers.
Alcohol consumption and genetic variation in methylenetetrahydrofolate reductase and 5-methyltetrahydrofolate-homocysteine methyltransferase in relation to breast cancer risk.
Cancer Epidemiol Biomarkers Prev.2009; 18: 2453-2459
Several studies reported that dietary folate may modulate breast cancer risk through aberrant DNA methylation during the early stages of mammary gland development.
The methylenetetrahydrofolate reductase C677T mutation induces cell-specific changes in genomic DNA methylation and uracil misincorporation: a possible molecular basis for the site-specific cancer risk modification.
These high-penetrance genes play a key role in hereditary breast cancer; however, their potential effect on the association with other risk factors such as alcohol consumption is still controversial. BRCA1 is a potent inhibitor of ERα activity and ethanol both down-regulates the gene’s expression and enhances the receptor’s function.
The available evidence does not show an increased risk of breast cancer related to alcohol consumption among BRCA1 carriers, although it suggests a decreased risk among BRCA2 carriers (OR=0.41, 95% CI=0.22, 0.77) associated with a modest alcohol intake.
Overall, the evidence is still limited because of the small number of study subjects. Nevertheless, further studies elucidating the contribution of environmental determinants to hereditary breast cancer could have major implications for cancer prevention in high-risk families.
Conclusion
Recent publications add to the current body of evidence that consumption of alcoholic beverages is causally associated to cancer of the female breast, even at low levels of alcohol consumption.
Current data indicate that breast cancer risk does not vary by beverage type and strengthen the evidence that ethanol is the main causal factor; nevertheless, other compounds present in various alcoholic beverages may play a role in, or prevent, the development of breast cancer. Polymorphisms in genes involved in the formation and detoxification of ethanol metabolites are known to modulate the risk of cancer at other sites, and could modulate the association of alcohol consumption with breast cancer risk; however, at present, results are controversial and do not allow the identification of susceptibility alleles for breast cancer subtypes. Experimental and epidemiologic studies show that alcohol-induced breast cancer may be related to an enhanced responsiveness to ER, thus suggesting that the association may be stronger for exposure during adolescence and early adulthood. In addition, there is growing evidence of an environmental impact on the breast cancer epigenome through nutrition. The MTHFR polymorphism appears to play a role via a folate-dependent epigenetic mechanism also modified by ethanol and possibly by menopausal status. However, the precise targets of epigenetic deregulation in breast cancer are still unclear; the field is rapidly expanding and additional data may allow the identification of specific methylation signatures.
Future Perspective
Better standardization in measuring the amount of alcohol intake and drinking pattern, improved knowledge of the relevant window of exposure, information on the presence of genetic polymorphisms modulating the effects of alcohol, and the estimation of the interaction of alcohol with nutrients such as folate will prove extremely valuable in terms of breast cancer prevention. Such information will improve our understanding of the mechanisms by which alcohol consumption increases breast cancer risk and of the heterogeneity observed across studies; thus also allowing to more accurately estimate breast cancer risk at different age stages, and to quantify the effect of hazardous drinking patterns. Understanding individual attitudes toward alcohol drinking and the influence of cultural and social factors will improve our assessment of the impact of alcohol drinking to tailor public health messages toward most susceptible population subgroups.
Acknowledgments
This research and the publication of this article were supported by the Health General directorate of the French Ministry of Health.
The publication of this supplement was made possible through the CDC and the Association for Prevention Teaching and Research (APTR) Cooperative Agreement No. 1 U360E000005-01. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC or the APTR.
No financial disclosures were reported by the authors of this paper.
Social inequalities in alcohol consumption and alcohol-related problems in the study countries of the EU concerted action “Gender, Culture and Alcohol Problems: a Multi-national Study.”.
Alcohol, tobacco and breast cancer—collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease.
Association of lifestyle and other risk factors with breast cancer according to menopausal status: a case-control study in the Region of Western Pomerania (Poland).
Dietary patterns and risk of cancer of various sites in the Norwegian European Prospective Investigation into Cancer and Nutrition cohort: the Norwegian Women and Cancer study.
Class I alcohol dehydrogenase is highly expressed in normal human mammary epithelium but not in invasive breast cancer: implications for breast carcinogenesis.
Relationship between potentially modifiable lifestyle factors and risk of second primary contralateral breast cancer among women diagnosed with estrogen receptor-positive invasive breast cancer.
Interaction of genetic polymorphisms in cytochrome P450 2E1 and glutathione S-transferase M1 to breast cancer in Taiwanese woman without smoking and drinking habits.
Haplotype patterns in cancer-related genes with long-range linkage disequilibrium: no evidence of association with breast cancer or positive selection.
High prevalence of hyperhomocysteinemia in chronic alcoholism: the importance of the thermolabile form of the enzyme methylenetetrahydrofolate reductase (MTHFR).
Is concordance with World Cancer Research Fund/American Institute for Cancer Research guidelines for cancer prevention related to subsequent risk of cancer? Results from the EPIC study.
Alcohol consumption and genetic variation in methylenetetrahydrofolate reductase and 5-methyltetrahydrofolate-homocysteine methyltransferase in relation to breast cancer risk.
Cancer Epidemiol Biomarkers Prev.2009; 18: 2453-2459
The methylenetetrahydrofolate reductase C677T mutation induces cell-specific changes in genomic DNA methylation and uracil misincorporation: a possible molecular basis for the site-specific cancer risk modification.
2 allele showed a protective effect on alcohol-related breast cancer risk.
00646-6&id=gr1.jpg){kind=link}