Female Breast Cancer and Alcohol Consumption

A Review of the Literature

Chiara Scoccianti, PhD, Batrice Lauby-Secretan, PhD, Pierre-Yves Bello, MD, MPH,
Vronique Chajes, PhD, Isabelle Romieu, MD, MPH, ScD
Context: Consumption of alcoholic beverages is one of the single most important known and
modiable 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 doseresponse
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
identied 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 inuence 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 quantication of the effects of occasional heavy
drinking and the identication of a window of higher susceptibility to breast cancer development.
(Am J Prev Med 2014;46(3S1):S16S25) & 2014 Published by Elsevier Inc. on behalf of American Journal of
Preventive Medicine

Introduction

onsumption of alcoholic beverages has been

linked to a large number of health impairments,
chronic diseases, and death worldwide.1 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.2
From the Nutritional Epidemiology Group (Scoccianti, Chajes, Romieu),
IARC Monographs Program Section (Lauby-Secretan), International
Agency for Research on Cancer, Lyon; Addictions Bureau (Bello), Health
General Directorate, Paris, France
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. E-mail:
romieui@iarc.fr.
0749-3797/$36.00
http://dx.doi.org/10.1016/j.amepre.2013.10.031

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Twenty years later, the causal relationship with cancer

was established also for low and moderate alcohol
intakes, and at several additional sites.3,4 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 ndings. Concerning the

Am J Prev Med 2014;46(3S1):S16S25 & 2014 Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine

Scoccianti et al / Am J Prev Med 2014;46(3S1):S16S25

relationship between alcohol consumption and breast

cancer, the underlying biological mechanisms are not
well dened. 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,5 alcohol-related
breast cancer is an important public health issue. The
total percentage of alcohol-attributable breast cancer
cases is estimated at 5% (95% CI2%, 8%) among
women in eight European countries.6
At present, several aspects of the association of alcohol
consumption with breast cancer risk are not fully
elucidated. Since the most recent IARC Monograph,4
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 (exemplied 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.

Alcohol intake, drinking habits, type of

alcoholic beverages

ALCOHOL
Ethanol, polyphenols, etc.

Evidence Acquisition
The present review is an update of the most recent IARC
Monograph on alcoholic beverages.3 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-Stransferases), BRCA (breast cancersusceptibility 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.3 Most cohort714 and casecontrol
studies1520 reported a linear doseresponse 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).8,21,22 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.21 Those few studies
that reported a nonsigniDNA methylation
cant or null association
included a small number
Folate pathway
of drinkers compared with
nondrinkers, lacked quantitative assessment of alcohol intake, or did not
adjust for potential conADHs, ALDHs, GSTM1, GSTTs
founders.2325

Acetaldehyde

Acetate

Breast cancer

Menopausal status
Hormonal pathway

BRCA mutations

Figure 1. Modifying 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
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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
201C) or in ethanol intake

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Table 1. Breast cancer risk by dimensions of alcohol consumption and by main modifying factors
Dimensions of alcohol consumption

Study; study design

Types of alcoholic beverage

Allen (2009) ; cohort study

Zhang (2007) ; WHS cohort study

p for trend

Wine

1.10 (1.07, 1.14)

Other drinks

1.12 (1.09, 1.15)

Beer

1.15 (1.03, 1.28)

White wine

1.13 (1.00, 1.27)

Red wine

1.08 (0.88, 1.34)

Liquor

1.08 (0.98, 1.19)

Liu (2012)40;

Young adulthood (1822 years)

NHS II cohort study

None

1.00 (ref)

10 g/day

1.15 (1.03, 1.28)

Z15 g/day

1.35 (1.01, 1.81)

None

1.00 (ref)

12 drinks/day in a month

1.08 (1.02, 1.16)

35 drinks/day in a month

1.16 (1.07, 1.27)

Z6 drinks/day in a month

1.33 (1.11, 1.59)

36

Chen (2011) ; NHS cohort study

Not signicant

0.03

o0.001

Main modifying factors

Hormones expression

For 10 g/day
55

Suzuki (2008) ; meta-analysis

www.ajpmonline.org

Menopausal status

p for heterogeneity among studies, 0.09

ER

1.12 (1.08, 1.15)

ERPR

1.11 (1.07, 1.14)

ERPR

1.15 (1.02, 1.30)

ER

1.07 (1.00, 1.14)

ERPR

1.04 (0.76, 1.43)

ERPR

1.04 (0.98, 1.09)

For 10 g/day
36

Chen (2011) ; NHS cohort study

Premenopausal

1.08 (1.00, 1.18)

Postmenopausal

1.07 (1.03, 1.10)

(continued on next page)

Scoccianti et al / Am J Prev Med 2014;46(3S1):S16S25

Occasional heavy drinking

Relative risk (95% CI)

For 10 g/day
21

Age at start drinking

Exposure category

March 2014

1.00 (ref)

1.08 (0.87, 1.35)

1.14 (0.78, 1.67)

1.34 (0.81, 2.23)

CC (wild-type)

CT

TT

TT (455 years)

Ericson (2009) ; cohort study

MTHFR (677TT variant)

1.01 (0.97, 1.06)

ADH1C (*1 vs *2)

85

Wang (2012); meta-analysis

1.05 (0.96, 1.16)

ADH1C (*1 vs *2)
Mao (2012) ; meta-analysis
Polymorphisms: Ethanol metabolism

77

ADH, alcohol dehydrogenase; ER, estrogen receptor; MTHFR, methylenetetrahydrofolate reductase; NHS, Nurses Health Study; PR, progesterone receptor; WHS, Womens Health Study

1.09 (1.01, 1.16)

Postmenopausal

0.03

p for interaction, 0.68

1.12 (0.99, 1.25)
Premenopausal
Zhang (2007); WHS cohort study

p for trend
Dimensions of alcohol consumption

Table 1. (continued)

Study; study design

Exposure category

Relative risk (95% CI)

Scoccianti et al / Am J Prev Med 2014;46(3S1):S16S25

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(number of drinks per time-period, typically per day or per

week; one drink is equivalent to 1012 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.3 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 rm
conclusions about safe levels of alcohol intake.21,26,27
Nevertheless, it has been recommended that women
should not exceed 12 drinks/day.2830
Types of alcoholic beverage. 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.15,21 However,
spirits such as Calvados contain high concentrations of
the carcinogenic acetaldehyde31 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.32 In experimental settings, these natural
phenolic compounds were shown to inhibit the activity
of aromatase or to alter DNA methylation after exposure to ethanol.33,34 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 rst full-term pregnancy,35,36 and thus differentially modulate breast cancer risk over a womans
lifetime.37 A limited number of studies have investigated
the presence of a window of higher susceptibility to alcoholrelated carcinogenesis. In utero exposure of rats leads to an
increased frequency of malignant mammary tumors in
offspring.38,39 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.40 Similar results are
observed at a higher drinking frequency and are consistent
with the hypothesis that alcohol carcinogens may

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preferentially act during mammary development.41 ERpositive 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.42 However, a detailed prospective analysis of the NHS
study and of a large Danish cohort of postmenopausal
women could not conrm a difference in risk according to
age at start drinking.36,43 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 ndings support the
hypothesis that timing of exposure to alcohol carcinogens
affects breast tumorigenesis, without however enabling the
identication 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 Z60 g of pure alcohol on at least one occasion in the
past 7 days44 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.4547 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.8 The Nurses Health Study reported that female
binge drinkers had an increased RR for breast cancer of
1.33 (95% CI1.11, 1.59) compared with other women.36
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
difcult. 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.48

Main Effect Modiers

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 detoxied 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.49 Acetaldehyde is capable of inducing DNA strand deletions,
chromosomal aberrations, and generating protein and
DNA adducts.50 Both ethanol and acetaldehyde interfere
with estrogen pathways and may trigger the expression of
hormone receptors (e.g., estrogen, prolactin receptors) in
breast tumors,51 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.5254 The major clinical breast
cancer subtypes, classied 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.7,12,5558 In a meta-analysis, Suzuki and colleagues59 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 colleagues60 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.61 Together these results
indicate that alcohol consumption increases breast cancer
risk by inducing the expression of ER and PR hormone
receptors.62 Nevertheless, the estrogen-dependent pathway
cannot solely explain the positive association between
alcohol consumption and ER tumors, and the underlying
biological mechanisms need further clarication.
Menopausal status. A different association of breast
cancer risk with alcohol drinking among pre- and postmenopausal women has been frequently advocated
because the large majority of breast cancers, and in
particular those occurring after menopause, are hormonedependent.63 Elevated levels of endogenous sex hormones
have been repeatedly associated with an increased risk of
breast cancer.7,6466 Postmenopausal women who use
hormone replacement therapy (estrogen plus progestin)
show a signicant 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
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Scoccianti et al / Am J Prev Med 2014;46(3S1):S16S25

67

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., 1020 g),
relative risks range from 0.97 (95% CI0.23, 4.06) to 2.07
(95% CI1.57, 4.66) in postmenopausal women, versus
0.85 (95% CI0.31, 2.34) to 1.66 (95% CI0.90, 3.05) in
premenopausal women.7,20,36,55,68 At present, the available
evidence does not show that menopausal status alone is a
signicant modier of the association between alcohol
consumption and breast cancer.7,8,25,56,69

Polymorphisms in Genes Involved in Ethanol

Metabolism and Detoxication
Genes regulating alcohol metabolism. Polymorphisms
in genes that regulate acetaldehyde formation and
detoxication 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 ADH1B*2 allele showed a
protective effect on alcohol-related breast cancer risk.70 In
four other studies in Japan, the United Kingdom, and the U.
S., however, no signicant differences in the risk by ADH1B
polymorphism were observed.56,69,71,72 No signicant association with the *5B/*5B genotype73,74 or the ALDH2
mutation,74,75 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.76,77
In some studies, the association was more pronounced
among premenopausal women,78 or among regular heavy
drinkers,56 but these results were not always replicated.69,79 In
addition, recent meta-analyses failed to show an increased
risk of breast cancer in ADH1C *1/*1 allele carriers either in
Caucasian or in Chinese populations.77,80 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.81 However, recent ndings do
not fully support a protective role of the GST isoenzymes on
alcohol-related breast cancer risk.82
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
March 2014

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one-carbon metabolism pathway, DNA synthesis, and cell

replication. Folate deciency leads to misincorporation of
uracil, chromosomal instability, and DNA hypomethylation, causing altered gene expression and thus contributing
to cancer development.83 Exposure to alcohol may deregulate the metabolism and levels of folate depending on
polymorphic variants of enzymes involved in one-carbon
metabolism.9,8486 In heavy and regular alcohol drinkers,
increased degradation of vitamin B, or folate deciency,
are reported, most likely because of a folate-poor diet and
to intestinal malabsorption, decreased liver uptake, and
increased urinary excretion of folic acid.87 Several cohort
studies report that high blood folate levels may play a
protective role on breast cancer risk related to alcohol
consumption,7,41,88 in particular among postmenopausal
women.89 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.90 On the other hand, some studies report
that the protective effect of high folate intake is either
null79,12,25,56,69,91; limited to women with high alcohol
consumption (Z4 drinks/day)92; or inversed among pre-/
peri-menopausal ER women.64,65 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 individuals interaction with dietary folate
intake. The MTHFR gene is the best studied for cancer
susceptibility.93,94 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.9598 The effect modication of the 677T polymorphism on breast cancer development99,100 is
observed in particular after menopause.85,86 Individuals
homozygous for the MTHFR 677T variant show
increased breast cancer risk at more than 2 drinks/day
compared with nondrinkers.94 Several studies reported
that dietary folate may modulate breast cancer risk
through aberrant DNA methylation during the early
stages of mammary gland development.95,96 Also, breast
cancer MTHFR 677T cells showed genomic DNA hypomethylation, a characteristic of most cancers, when folate
supply was adequate or high.101

BRCA1/BRCA2 and Hereditary Breast Cancer

The BRCA1 and BRCA2 genes help to ensure DNA
stability and to prevent uncontrolled cell growth in wild-

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102

type cells. 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 ER activity and ethanol both down-regulates
the genes expression and enhances the receptors function.103 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 (OR0.41, 95% CI0.22,
0.77) associated with a modest alcohol intake.104,105 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 detoxication 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 identication of
susceptibility alleles for breast cancer subtypes. Experimental and epidemiologic studies show that alcoholinduced 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 modied by ethanol and possibly by menopausal status. However, the precise targets of epigenetic
deregulation in breast cancer are still unclear; the eld is
rapidly expanding and additional data may allow the
identication of specic 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 inuence 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.
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 ndings and conclusions in this report
are those of the authors and do not necessarily represent the
ofcial position of the CDC or the APTR.
No nancial disclosures were reported by the authors of
this paper.

References
1. WHO. Global health risks: mortality and burden of disease attributable to selected major risks, 2009. www.who.int/healthinfo/global_
burden_disease/GlobalHealthRisks_report_full.pdf.
2. WHO. International Agency for research in Cancer. IARC monograph on the evaluation of carcinogenic risks to humans.
monographs.iarc.fr/ENG/Monographs/vol86/mono86.pdf.
3. Secretan B, Straif K, Baan R, et al. A review of human carcinogens
Part E: tobacco, areca nut, alcohol, coal smoke, and salted sh. Lancet
Oncol 2009;10(11):10334.
4. Cogliano VJ, Baan R, Straif K, et al. Preventable exposures associated
with human cancers. J Natl Cancer Inst 2011;103(24):182739.
5. Bloomeld K, Grittner U, Kramer S, Gmel G. 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 Alcohol Suppl 2006;41
(1):i2636.
6. Schutze M, Boeing H, Pischon T, et al. Alcohol attributable burden of
incidence of cancer in eight European countries based on results from
prospective cohort study. BMJ 2011;342:d1584.
7. Zhang SM, Lee IM, Manson JE, Cook NR, Willett WC, Buring JE.
Alcohol consumption and breast cancer risk in the Womens Health
Study. Am J Epidemiol 2007;165(6):66776.
8. Morch LS, Johansen D, Thygesen LC, et al. Alcohol drinking,
consumption patterns and breast cancer among Danish nurses: a
cohort study. Eur J Public Health 2007;17(6):6249.
9. Duffy CM, Assaf A, Cyr M, et al. Alcohol and folate intake and breast
cancer risk in the WHI Observational Study. Breast Cancer Res Treat
2009;116(3):55162.

www.ajpmonline.org

Scoccianti et al / Am J Prev Med 2014;46(3S1):S16S25

10. Eriksson CJ. Measurement of acetaldehyde: what levels occur
naturally and in response to alcohol? Novartis Found Symp 2007;285:
24755.
11. Hamajima N, Hirose K, Tajima K, et al. Alcohol, tobacco and breast
cancercollaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and
95,067 women without the disease. Br J Cancer 2002;87(11):123445.
12. Lew JQ, Freedman ND, Leitzmann MF, et al. Alcohol and risk of
breast cancer by histologic type and hormone receptor status in
postmenopausal women: the NIH-AARP Diet and Health Study. Am
J Epidemiol 2009;170(3):30817.
13. Li Y, Baer D, Friedman GD, Udaltsova N, Shim V, Klatsky AL. Wine,
liquor, beer and risk of breast cancer in a large population. Eur J
Cancer 2009;45(5):84350.
14. Thygesen LC, Morch LS, Keiding N, Johansen C, Gronbaek M. Use of
baseline and updated information on alcohol intake on risk for breast
cancer: importance of latency. Int J Epidemiol 2008;37(3):66977.
15. Newcomb PA, Nichols HB, Beasley JM, et al. No difference between
red wine or white wine consumption and breast cancer risk. Cancer
Epidemiol Biomarkers Prev 2009;18(3):100710.
16. Beji NK, Reis N. Risk factors for breast cancer in Turkish women: a
hospital-based case-control study. Eur J Cancer Care (Engl) 2007;16
(2):17884.
17. Berstad P, Ma H, Bernstein L, Ursin G. Alcohol intake and breast cancer
risk among young women. Breast Cancer Res Treat 2008;108(1):11320.
18. Knight JA, Bernstein L, Largent J, et al. Alcohol intake and cigarette
smoking and risk of a contralateral breast cancer: the Womens
Environmental Cancer and Radiation Epidemiology Study. Am J
Epidemiol 2009;169(8):9628.
19. Kocic B, Petrovic B, Filipovic S. Risk factors for breast cancer: a
hospital-based case-control study. J BUON 2008;13(2):2314.
20. Kruk J. 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). Asian Pac J Cancer Prev
2007;8(4):51324.
21. Allen NE, Beral V, Casabonne D, et al. Moderate alcohol intake and
cancer incidence in women. J Natl Cancer Inst 2009;101(5):296305.
22. Ellison RC, Zhang Y, McLennan CE, Rothman KJ. Exploring the
relation of alcohol consumption to risk of breast cancer. Am J
Epidemiol 2001;154(8):7407.
23. Brown LM, Gridley G, Wu AH, et al. Low level alcohol intake,
cigarette smoking and risk of breast cancer in Asian-American
women. Breast Cancer Res Treat 2010;120(1):20310.
24. Engeset D, Dyachenko A, Ciampi A, Lund E. 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. Eur J Cancer Prev 2009;18(1):6975.
25. Kabat GC, Miller AB, Jain M, Rohan TE. Dietary intake of selected B
vitamins in relation to risk of major cancers in women. Br J Cancer
2008;99(5):81621.
26. Sanchez-Lopez MP, Cuellar-Flores I, Dresch V. The impact of gender
roles on health. Women Health 2012;52(2):18296.
27. Furtwaengler NA, de Visser RO. Lack of international consensus in
low-risk drinking guidelines. Drug Alcohol Rev 2013;32(1):118.
28. European Commission. European Code Against Cancer. www.european
cancerleagues.org/images/stories/Ann_Oncol-2003-Boyle-973-1005.pdf.
29. World Cancer Research Fund/American Institute for Cancer
Research. Food, nutrition, physical activity and the prevention of
cancer: a global perspective. Washington DC: AICR, 2007.
30. Canadian Centre on Substance Abuse. Canadas low-risk alcohol
drinking guidelines. 2012. www.ccsa.ca/Eng/Priorities/Alcohol/
Canada-Low-Risk-Alcohol-Drinking-Guidelines/Pages/default.aspx.
31. Linderborg K, Joly JP, Visapaa JP, Salaspuro M. Potential mechanism
for Calvados-related oesophageal cancer. Food Chem Toxicol
2008;46(2):4769.

March 2014

S23

32. Shufelt C, Merz CN, Yang Y, et al. Red versus white wine as a
nutritional aromatase inhibitor in premenopausal women: a pilot
study. J Womens Health (Larchmt ) 2012;21(3):2814.
33. Kiskova T, Ekmekcioglu C, Garajova M, et al. A combination of
resveratrol and melatonin exerts chemopreventive effects in
N-methyl-N-nitrosourea-induced rat mammary carcinogenesis. Eur
J Cancer Prev 2012;21(2):16370.
34. Zhu W, Qin W, Zhang K, et al. Trans-resveratrol alters mammary
promoter hypermethylation in women at increased risk for breast
cancer. Nutr Cancer 2012;64(3):393400.
35. Terry MB, Zhang FF, Kabat G, et al. Lifetime alcohol intake and
breast cancer risk. Ann Epidemiol 2006;16(3):23040.
36. Chen WY, Rosner B, Hankinson SE, Colditz GA, Willett WC.
Moderate alcohol consumption during adult life, drinking patterns,
and breast cancer risk. JAMA 2011;306(17):188490.
37. Onland-Moret NC, Peeters PH, van der Schouw YT, Grobbee DE,
van Gils CH. Alcohol and endogenous sex steroid levels in
postmenopausal women: a cross-sectional study. J Clin Endocrinol
Metab 2005;90(3):14149.
38. Polanco TA, Crismale-Gann C, Reuhl KR, Sarkar DK, Cohick WS.
Fetal alcohol exposure increases mammary tumor susceptibility and
alters tumor phenotype in rats. Alcohol Clin Exp Res 2010;34(11):
187987.
39. Stevens RG, Hilakivi-Clarke L. Alcohol exposure in utero and breast
cancer risk later in life. Alcohol Alcohol 2001;36(3):2767.
40. Liu Y, Tamimi RM, Berkey CS, et al. Intakes of alcohol and folate
during adolescence and risk of proliferative benign breast disease.
Pediatrics 2012;129(5):e1192e1198.
41. Berkey CS, Willett WC, Frazier AL, et al. Prospective study of
adolescent alcohol consumption and risk of benign breast disease in
young women. Pediatrics 2010;125(5):e1081e1087.
42. Russo J, Yang X, Hu YF, et al. Biological and molecular basis of
human breast cancer. Front Biosci 1998;3:D944D960.
43. Tjonneland A, Christensen J, Thomsen BL, et al. Lifetime alcohol
consumption and postmenopausal breast cancer rate in Denmark: a
prospective cohort study. J Nutr 2004;134(1):1738.
44. WHO. Global status report on alcohol and health 2011. http://www.
who.int/substance_abuse/publications/global_alcohol_report/en/.
45. Polednak AP. Recent trends in incidence rates for selected alcoholrelated cancers in the U.S. Alcohol Alcohol 2005;40(3):2348.
46. MacArthur GJ, Smith MC, Melotti R, et al. Patterns of alcohol use
and multiple risk behaviour by gender during early and late
adolescence: the ALSPAC cohort. J Public Health (Oxf) 2012;34(S1):
i2030.
47. Rebholz CE, Kuehni CE, Strippoli MP, et al. Alcohol consumption
and binge drinking in young adult childhood cancer survivors.
Pediatr Blood Cancer 2012;58(2):25664.
48. Giovannucci E, Stampfer MJ, Colditz GA, et al. Recall and selection
bias in reporting past alcohol consumption among breast cancer
cases. Cancer Causes Control 1993;4(5):4418.
49. Triano EA, Slusher LB, Atkins TA, et al. Class I alcohol dehydrogenase is highly expressed in normal human mammary epithelium but
not in invasive breast cancer: implications for breast carcinogenesis.
Cancer Res 2003;63(12):3092100.
50. Seitz HK, Stickel F. Acetaldehyde as an underestimated risk factor for
cancer development: role of genetics in ethanol metabolism. Genes
Nutr 2010;5(2):1218.
51. Seitz HK, Stickel F. Molecular mechanisms of alcohol-mediated
carcinogenesis. Nat Rev Cancer 2007;7(8):599612.
52. Singletary KW, Gapstur SM. Alcohol and breast cancer: review of
epidemiologic and experimental evidence and potential mechanisms.
JAMA 2001;286:214351.
53. Dorgan JF, Baer DJ, Albert PS, et al. Serum hormones and the
alcohol-breast cancer association in postmenopausal women. J Natl
Cancer Inst 2001;93(9):7105.

S24

Scoccianti et al / Am J Prev Med 2014;46(3S1):S16S25

54. Missmer SA, Eliassen AH, Barbieri RL, Hankinson SE. Endogenous
estrogen, androgen, and progesterone concentrations and breast
cancer risk among postmenopausal women. J Natl Cancer Inst
2004;96(24):185665.
55. Suzuki R, Orsini N, Mignone L, Saji S, Wolk A. Alcohol intake and
risk of breast cancer dened by estrogen and progesterone receptor
statusa meta-analysis of epidemiological studies. Int J Cancer
2008;122(8):183241.
56. Terry MB, Knight JA, Zablotska L, et al. Alcohol metabolism, alcohol
intake, and breast cancer risk: a sister-set analysis using the Breast
Cancer Family Registry. Breast Cancer Res Treat 2007;106(2):2818.
57. Chlebowski RT, Anderson GL, Lane DS, et al. Predicting risk of
breast cancer in postmenopausal women by hormone receptor status.
J Natl Cancer Inst 2007;99(22):1695705.
58. Setiawan VW, Monroe KR, Wilkens LR, Kolonel LN, Pike MC,
Henderson BE. Breast cancer risk factors dened by estrogen and
progesterone receptor status: the multiethnic cohort study. Am J
Epidemiol 2009;169(10):12519.
59. Suzuki R, Orsini N, Saji S, Key TJ, Wolk A. Body weight and
incidence of breast cancer dened by estrogen and progesterone
receptor statusa meta-analysis. Int J Cancer 2009;124(3):698712.
60. Barnes BB, Steindorf K, Hein R, Flesch-Janys D, Chang-Claude J.
Population attributable risk of invasive postmenopausal breast cancer
and breast cancer subtypes for modiable and non-modiable risk
factors. Cancer Epidemiol 2011;35(4):34552.
61. Trivers KF, Lund MJ, Porter PL, et al. The epidemiology of triple-negative
breast cancer, including race. Cancer Causes Control 2009;20(7):107182.
62. Fernandez SV. Estrogen, alcohol consumption, and breast cancer.
Alcohol Clin Exp Res 2011;35(3):38991.
63. Feigelson HS, Kean-Cowdin R, Coetzee GA, Stram DO, Kolonel LN,
Henderson BE. Building a multigenic model of breast cancer
susceptibility: CYP17 and HSD17B1 are two important candidates.
Cancer Res 2001;61(2):7859.
64. Deandrea S, Talamini R, Foschi R, et al. Alcohol and breast cancer
risk dened by estrogen and progesterone receptor status: a casecontrol study. Cancer Epidemiol Biomarkers Prev 2008;17(8):20258.
65. Lin J, Lee IM, Cook NR, et al. Plasma folate, vitamin B-6, vitamin B-12,
and risk of breast cancer in women. Am J Clin Nutr 2008;87(3):73443.
66. Petri AL, Tjonneland A, Gamborg M, et al. Alcohol intake, type of
beverage, and risk of breast cancer in pre- and postmenopausal
women. Alcohol Clin Exp Res 2004;28(7):108490.
67. Horn-Ross PL, Canchola AJ, West DW, et al. Patterns of alcohol
consumption and breast cancer risk in the California Teachers Study
cohort. Cancer Epidemiol Biomarkers Prev 2004;13(3):40511.
68. Li CI, Daling JR, Porter PL, Tang MT, Malone KE. Relationship between
potentially modiable lifestyle factors and risk of second primary
contralateral breast cancer among women diagnosed with estrogen
receptor-positive invasive breast cancer. J Clin Oncol 2009;27(32):53128.
69. Visvanathan K, Crum RM, Strickland PT, et al. Alcohol dehydrogenase genetic polymorphisms, low-to-moderate alcohol consumption,
and risk of breast cancer. Alcohol Clin Exp Res 2007;31(3):46776.
70. Lilla C, Koehler T, Kropp S, Wang-Gohrke S, Chang-Claude J.
Alcohol dehydrogenase 1B (ADH1B) genotype, alcohol consumption
and breast cancer risk by age 50 years in a German case-control
study. Br J Cancer 2005;92(11):203941.
71. Cox A, Dunning AM, Garcia-Closas M, et al. A common coding
variant in CASP8 is associated with breast cancer risk. Nat Genet
2007;39(3):3528.
72. Kawase T, Matsuo K, Hiraki A, et al. Interaction of the effects of
alcohol drinking and polymorphisms in alcohol-metabolizing
enzymes on the risk of female breast cancer in Japan. J Epidemiol
2009;19(5):24450.
73. Choi JY, Abel J, Neuhaus T, et al. Role of alcohol and genetic
polymorphisms of CYP2E1 and ALDH2 in breast cancer development. Pharmacogenetics 2003;13(2):6772.

74. Wu SH, Tsai SM, Hou MF, et al. Interaction of genetic polymorphisms in cytochrome P450 2E1 and glutathione S-transferase
M1 to breast cancer in Taiwanese woman without smoking and
drinking habits. Breast Cancer Res Treat 2006;100:938.
75. Ribas G, Milne RL, Gonzalez-Neira A, Benitez J. Haplotype patterns
in cancer-related genes with long-range linkage disequilibrium: no
evidence of association with breast cancer or positive selection. Eur J
Hum Genet 2008;16:25260.
76. Coutelle C, Hohn B, Benesova M, et al. Risk factors in alcohol
associated breast cancer: alcohol dehydrogenase polymorphism and
estrogens. Int J Oncol 2004;25(4):112732.
77. Mao Q, Gao L, Wang H, Wang Q, Zhang T. The alcohol dehydrogenase 1C(rs698) genotype and breast cancer: a meta-analysis. Asia Pac J
Public Health 2012 May 31[Epub ahead of print].
78. Terry MB, Gammon MD, Zhang FF, et al. ADH3 genotype, alcohol
intake and breast cancer risk. Carcinogenesis 2006;27(4):8407.
79. Breast Cancer Association Consortium. Commonly studied singlenucleotide polymorphisms and breast cancer: results from the Breast
Cancer Association Consortium. J Natl Cancer Inst 2006;98(19):138296.
80. Wang L, Zhang Y, Ding D, He X, Zhu Z. Lack of association of ADH1C
genotype with breast cancer susceptibility in Caucasian population: a
pooled analysis of case-control studies. Breast 2012;21(4):4359.
81. Zheng T, Holford TR, Zahm SH, et al. Glutathione S-transferase M1
and T1 genetic polymorphisms, alcohol consumption and breast
cancer risk. Br J Cancer 2003;88(1):5862.
82. Sergentanis TN, Economopoulos KP. GSTT1 and GSTP1 polymorphisms and breast cancer risk: a meta-analysis. Breast Cancer
Res Treat 2010;121(1):195202.
83. Duthie SJ, Narayanan S, Brand GM, Pirie L, Grant G. Impact of folate
deciency on DNA stability. J Nutr 2002;132(8S):2444S2449S.
84. de la Vega MJ, Santolaria F, Gonzalez-Reimers E, et al. High
prevalence of hyperhomocysteinemia in chronic alcoholism: the
importance of the thermolabile form of the enzyme methylenetetrahydrofolate reductase (MTHFR). Alcohol 2001;25(2):5967.
85. Ericson U, Sonestedt E, Ivarsson MI, et al. Folate intake, methylenetetrahydrofolate reductase polymorphisms, and breast cancer risk
in women from the Malmo Diet and Cancer cohort. Cancer
Epidemiol Biomarkers Prev 2009;18(4):110110.
86. Sellers TA, Grabrick DM, Vierkant RA, et al. Does folate intake
decrease risk of postmenopausal breast cancer among women with a
family history? Cancer Causes Control 2004;15(2):11320.
87. Halsted CH, Villanueva JA, Devlin AM, Chandler CJ. Metabolic
interactions of alcohol and folate. J Nutr 2002;132(8S):2367S272S.
88. Stolzenberg-Solomon RZ, Chang SC, Leitzmann MF, et al. Folate
intake, alcohol use, and postmenopausal breast cancer risk in the
Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Am J
Clin Nutr 2006;83(4):895904.
89. Lajous M, Lazcano-Ponce E, Hernandez-Avila M, Willett W, Folate
Romieu I. vitamin B(6), and vitamin B(12) intake and the risk of
breast cancer among Mexican women. Cancer Epidemiol Biomarkers
Prev 2006;15(3):4438.
90. Romaguera D, Vergnaud AC, Peeters PH, et al. 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. Am J Clin Nutr 2012;96(1):
15063.
91. Stevens VL, McCullough ML, Sun J, Gapstur SM. Folate and other
one-carbon metabolism-related nutrients and risk of postmenopausal
breast cancer in the Cancer Prevention Study II Nutrition Cohort.
Am J Clin Nutr 2010;91(6):170815.
92. Baglietto L, English DR, Gertig DM, Hopper JL, Giles GG. Does
dietary folate intake modify effect of alcohol consumption on breast
cancer risk? Prospective cohort study. BMJ 2005;331(7520):807.
93. Tokgozoglu SL, Alikasifoglu M, Unsal, et al. Methylene tetrahydrofolate reductase genotype and the risk and extent of coronary artery

www.ajpmonline.org

Scoccianti et al / Am J Prev Med 2014;46(3S1):S16S25

94.

95.

96.

97.

98.
99.

disease in a population with low plasma folate. Heart 1999;81(5):

51822.
Platek ME, Shields PG, Marian C, et al. 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(9):24539.
Christensen BC, Kelsey KT, Zheng S, et al. Breast cancer DNA
methylation proles are associated with tumor size and alcohol and
folate intake. PLoS Genet 2010;6(7):e1001043.
Sangrajrang S, Sato Y, Sakamoto H, Ohnami S, Khuhaprema T,
Yoshida T. Genetic polymorphisms in folate and alcohol metabolism
and breast cancer risk: a case-control study in Thai women. Breast
Cancer Res Treat 2010;123(3):88593.
Tao MH, Marian C, Shields PG, et al. Alcohol consumption in
relation to aberrant DNA methylation in breast tumors. Alcohol
2011;45(7):68999.
Huang Y, Nayak S, Jankowitz R, Davidson NE, Oesterreich S. Epigenetics
in breast cancer: whats new? Breast Cancer Res 2011;13(6):225.
Alshatwi AA. Breast cancer risk, dietary intake, and methylenetetrahydrofolate reductase (MTHFR) single nucleotide polymorphisms. Food Chem Toxicol 2010;48(7):18815.

March 2014

S25

100. Shrubsole MJ, Gao YT, Cai Q, et al. MTHFR polymorphisms, dietary
folate intake, and breast cancer risk: results from the Shanghai Breast
Cancer Study. Cancer Epidemiol Biomarkers Prev 2004;13(2):1906.
101. Sohn KJ, Jang H, Campan M, et al. The methylenetetrahydrofolate
reductase C677T mutation induces cell-specic changes in genomic
DNA methylation and uracil misincorporation: a possible molecular
basis for the site-specic cancer risk modication. Int J Cancer
2009;124(9):19992005.
102. Cornelisse CJ, Cornelis RS, Devilee P. Genes responsible for familial
breast cancer. Pathol Res Pract 1996;192(7):68493.
103. Fan S, Meng Q, Gao B, et al. Alcohol stimulates estrogen receptor
signaling in human breast cancer cell lines. Cancer Res 2000;60(20):
56359.
104. McGuire V, John EM, Felberg A, et al. No increased risk of breast
cancer associated with alcohol consumption among carriers of
BRCA1 and BRCA2 mutations ages o50 years. Cancer Epidemiol
Biomarkers Prev 2006;15(8):15657.
105. Dennis J, Krewski D, Cote FS, Fafard E, Little J, Ghadirian P. Breast
cancer risk in relation to alcohol consumption and BRCA gene
mutationsa case-only study of gene-environment interaction.
Breast J 2011;17(5):47784.