Links Between Alcohol Consumption and Breast Cancer

A Look at the Evidence

Ying Liu; Nhi Nguyen; Graham A Colditz


Women's Health. 2015;11(1):65-77. 

In This Article

Possible Mechanisms

Despite a consistent association between alcohol consumption and breast cancer risk, the underlying mechanisms remain unclear. The most commonly investigated pathways include the effect of alcohol on circulating estrogen levels and ER in mammary epithelial cells and the carcinogenic role of ethanol metabolites. Recent in vivo and in vitro studies suggest other mechanisms through which alcohol may play a role in breast tumorigenesis, such as the effect of alcohol on epithelial–mesenchymal transition (EMT), epithelium–stroma interaction and epigenetic regulation of gene expression in the breast.

Estrogen & ER

Prolonged exposure to estrogens has been related to the elevated incidence of breast cancer in humans. Epidemiologic studies in postmenopausal women receiving hormonal therapy (HT) have revealed that high levels of estrogen in blood are associated with elevated risk of subsequent breast cancer.[81,82] Mammary adenocarcinomas were induced in rats continuously exposed to supraphysiological doses of estrogens, while fibroadenomas were found in rats dosed with low estrogen levels over long periods of time.[83,84] The proliferative effect of estrogens on breast epithelial cells is considered to be mediated by its nuclear receptor, ER-α.[85] However, estrogen may induce breast cancer through a genotoxic, ER-α-independent pathway.[86–89]

In premenopausal adult women, alcohol intake has been associated with higher circulating levels of estradiol and estrone.[90–92] A controlled diet study reported that consumption of 30 g ethanol (~2.5 drinks) per day for three menstrual cycles was associated with a 28% increase in plasma estradiol and a 21% increase in plasma estrone among women ages 21–40 years.[93] The alcohol-related increase in plasma estradiol was restricted to women using oral contraceptives in another controlled diet study.[94] In addition, a shorter menstrual cycle was reported by premenopausal women with moderate alcohol consumption as compared with nondrinkers, suggesting an increased exposure to endogenous estrogens.[95] For adolescent girls, the impact of alcohol consumption on sex hormone levels remains unclear. Martin et al.[96] reported that alcohol use was positively related to blood estradiol and testosterone levels among girls in high schools. In contrast, Block et al.[97] reported that moderate alcohol consumption lowered estrogen levels in adolescent girls ages 12–18 years.

A recent meta-analysis of eight prospective studies among postmenopausal women showed that alcohol intake is positively associated with all the sex hormones, with the strongest association for dehydroepiandrosterone sulfate (DHEAS), but inversely associated with sex hormone-binding globulin.[98] DHEAS is an androgen and can be metabolized to estrogen in the breast by aromatase. In a randomized trial including 51 postmenopausal women without HT, serum estrone sulfate and DHEAS were increased by 8 and 5% in women consuming 15 g of alcohol per day, respectively.[99] There is an even more pronounced effect of moderate alcohol intake on blood estradiol levels in postmenopausal women who were taking HT. Compared with nondrinkers using estrogen, postmenopausal women who consumed 15.6 g of alcohol per week and took 1 mg of estradiol daily had a 3.3-fold increase in serum estradiol levels.[100] Alcohol may increase circulating sex hormone levels through an increase in the hepatic redox state and inhibition of the activity of sulfotransferase and 2-hydroxylase, resulting in a decrease in steroid degradation.[94,101] Another explanation is the increased aromatase activity following chronic alcohol consumption, which leads to an enhanced conversion of testosterone to estrogens.[102,103]

The elevated levels of intracellular estrogens resulting from alcohol intake may act through the ER to promote breast tumor growth. Ethanol stimulates proliferation of ER+ but not ER breast cancer cells, causing a 10- to 15-fold increase in transcriptional activity of ER.[104,105] Ethanol increases ER-α expression through the JNK1 pathway.[106] Several epidemiologic studies have shown that alcohol was more strongly associated with hormone-receptor-positive breast tumors than with other types of breast cancer,[10] consistent with an underlying hormonal basis for the association between alcohol intake and breast cancer. The risks for ER+/PR+ and ER+/PR breast cancer increased by 8% (95% CI: 2–15%) and 12% (95% CI: 0–25%), respectively, per drink consumed per day among postmenopausal women,[107] which is comparable to the 12% (95% CI: 8–15%) increase in risk of ER+ tumors per 10 g/day of alcohol consumption reported in a meta-analysis of four prospective studies and 16 case–control studies.[10] In the NHS cohort, alcohol consumption appeared to be more strongly associated with risk of ER+/PR+, ER+/PR than with risk of ER/PR, but the difference was not significant.[2] Among parous women in the NHS II, we found that alcohol consumption before first pregnancy tended to be more strongly related to risks of ER+/PR+ tumors (RR: 1.18; 95% CI: 1.03–1.34; pheterogeneity = 0.06) compared with the risks for ER+/PR tumors (RR: 0.86; 95% CI: 0.60–1.22) and ER/PR tumors (RR: 0.84; 95% CI: 0.60–1.16).[6] Together, these results support the hypothesis that alcohol may enhance breast tissue's sensitivity to estrogens and predominantly increase the risk of breast cancer expressing the hormone receptors.

Alcohol Metabolism

The ethanol-induced increase in sex hormones is thought to promote proliferation of already initiated mammary epithelial cells but not cause neoplastic transformation of normal epithelial cells.[108] Another possibility is related to carcinogenic products of alcohol metabolism. In the human body, alcohol is converted to acetaldehyde primarily by alcohol dehydrogenase and further to acetate by acetaldehyde dehydrogenase and xanthine oxidoreductase.[5,109] Acetaldehyde rapidly binds to DNA and proteins and produces DNA adducts, which results in DNA point mutations, DNA crosslinks and chromosomal aberrations.[110–112] In addition, acetaldehyde inhibits the repair of oxidative DNA damages induced by alkylating agents.[113]

Although liver is a primary site where acetaldehyde and free radicals are produced in the process of alcohol metabolism, normal human breast tissue has the capacity to metabolize ethanol at low concentrations and alcohol dehydrogenase is expressed in the human breast epithelial cells.[9,114] In rats, acetaldehyde accumulates in mammary tissue for prolonged periods of time after a single oral dose of ethanol and finally reaches a level considerably higher than in blood.[115,116] This is primarily due to increasing production of acetaldehyde in mammary tissue, the limited ability to detoxify acetaldehyde in mammary tissue and acetaldehyde produced elsewhere and delivered to mammary tissue via blood.[108]

In addition to acetaldehyde, reactive oxygen species (ROS) are derived from alcohol metabolism and have been implicated in alcohol-associated breast carcinogenesis. Similar to acetaldehyde, ROS can damage DNA by causing mutation and strand breaks.[109] ROS are involved in both the initiation and progression of cancer.[117] Xanthine oxidoreductase and aldehyde oxidase, two enzymes involved in acetaldehyde metabolism, can generate ROS and are also present in mammary tissue.[109] Thus, exposure to alcohol may increase oxidative DNA damage in breast tissue. This hypothesis is supported by a recent in vitro study in which alcohol-derived salsolinol significantly enhanced 8-oxo-dG formation, an indicator of oxidative damage, in normal mammary epithelial cells.[118] Elevated levels of 8-oxo-dG adducts in DNA play a fundamental role in breast cancer.[119]

Other Mechanisms

The EMT is essential for the normal development and also emerging as an important mechanism for cancer progression.[120] During the EMT, epithelial cells lose their polarity and tight cell–cell adhesion, and gain migratory and invasive properties to become mesenchymal cells. The EMT phenotype is characterized by upregulation of matrix metalloprotease (MMP) and vimentin but downregulation of E-cadherin. Forsyth et al.[121] reported that alcohol triggers EMT in breast cancer cells through EGFR–Snail signaling. The ethanol concentrations used in this study were equivalent to those that could be generated by moderate alcohol intake in humans.

Carcinogenic effects of ethanol may not only target breast epithelial cells. Ethanol may also affect stromal cells and interfere with the tumor–stroma interaction. MMPs enhance tumor invasion and metastasis by degrading the extracellular matrix and promoting cell migration.[122] High levels of MMP-2 and MMP-9 expression in tumor tissue have been correlated with enhanced metastasis and poor prognosis in breast cancer patients.[123–125] In most cases, these two MMPs are not produced by malignant epithelial cells, but by surrounding tumor stroma, particularly stromal fibroblasts.[126,127] Ethanol activates MMP-2 production by fibroblasts in a dose-dependent manner and culture medium collected from ethanol-exposed fibroblasts significantly alters the invasive behavior of breast cancer cells and mammary epithelial cells.[128] In addition, a recent in vitro study showed that ethanol promotes the adhesion of breast cancer cells to fibronectin, an important component of the extracellular matrix through suppression of the Nm23 metastatic suppressor gene and subsequent enhancement of fibronectin receptor ITGA5 expression.[129] Ethanol stimulates migration and invasion of breast cancer cells,[129] particularly those overexpressing HER2.[130] Breast tumors overexpressing HER2 account for about 20–30% of breast cancer cases and generally have poor prognosis.[131–135]

Emerging evidence suggests the impact of alcohol on epigenetic regulation of gene expression.[136] Epigenetic dysregulation is a key mechanism for tumor initiation and progression. Abnormal DNA methylation is the best understood epigenetic cause of disease. Global hypomethylation can result in chromosome instability, and region-specific hypermethylation has been linked with the silencing of tumor suppressor genes. Chronic alcohol intake has been linked to lower leukocyte DNA global methylation in humans.[137] In a study of the methylation profiles of breast tumors, Christensen et al.[138] showed a trend toward decreased methylation with increasing alcohol intake, and a trend toward increased methylation with increasing dietary folate. There were no individual CpG loci showing statistically significant alcohol-related changes in methylation in that study. However, other studies reported that alcohol consumption was related to altered methylation patterns for several genes, including hypermethylation of ER-α[139] and tumor suppressor gene E-cadherin and hypomethylation of p16.[140]

Several mechanisms may mediate the effect of alcohol on DNA methylation, including reduced folate bioavailability and inhibition of key enzymes in one-carbon metabolism that leads to reduced production of the major methyl donor S-adenosylmethionine.[5,136] In addition, alcohol and acetaldehyde affect methylation patterns by suppression of activity and expression of enzymes involved in DNA methylation. Alcohol can adversely affect folate metabolism by inhibiting the intestinal absorption, reducing the hepatic storage and increasing the renal excretion.[141] Folate, as a methyl donor in one-carbon metabolism, is essential for DNA synthesis and methylation. Several prospective studies showed that the adverse effect of alcohol consumption on breast cancer risk was restricted to women with low folate intake, and a protective effect of high folate intake (generally ≥600 μg/day) on breast cancer risk was observed primarily among women with high alcohol consumption.[142–146] However, our previous work showed that folate intake during adolescence did not reduce the risk of proliferative BBD associated with alcohol intake during adolescence and early adulthood among women in the NHS II.[49] This null finding could be due to the average level of folate intake (310 μg/day) in our sample that was too low to detect a modifying effect of folate on the risk for alcohol-associated proliferative BBD.