Executive Summary

Publication Details

Alcohol Consumption and Cancer Risk: Understanding Possible Mechanisms for Breast and Colorectal Cancers

The purpose of our assessment of alcohol and cancer induction is to explore the possible underlying causal mechanism(s) of the association between alcohol consumption and breast and colorectal cancers. Therefore, we developed four Key Questions that address the potential mechanism(s) by which alcohol might be involved in the development of breast and colorectal cancers. The primary evidence base to address these questions consisted of experimental studies of humans, animals, and cell lines where alcohol exposure could be controlled. In addition to this evidence base we also considered epidemiology studies where alcohol exposure was not controlled (including those in patients with or without cancer) and hypothesis-generating studies that examined potential metabolic pathways connecting alcohol to cancer risk. These studies were considered in a separate evidence base that did not directly address the Key Questions.

Methods

The following Key Questions will be addressed in this report:

  1. What are the likely causal mechanisms by which alcohol contributes to the development of breast cancer? Which of the possible mechanisms (e.g., induction of P450 cytochromes and carcinogen metabolism, effects on blood hormone concentrations, effect of acetaldehyde or other alcohol metabolite on apoptosis and DNA repair, interactive effects on other nutritional factors, or others) are likely to be most important in breast cancer development?
  2. For the most likely mechanisms of action involving alcohol and the development of breast cancer, how might other factors modify the effect of alcohol on breast cancer (for example, age, latency of effect, intensity, duration, and recency of exposure, presence of co-carcinogens, presence of threshold effect)? Do the causal mechanisms vary by cell type or other tumor characteristics?
  3. What are the likely causal mechanisms by which alcohol contributes to the development of colorectal cancer? Which of the possible mechanisms (e.g., induction of P450 cytochromes and carcinogen metabolism, effects on blood hormone concentrations, effect of acetaldehyde or other alcohol metabolite on apoptosis and DNA repair, interactive effects on other nutritional factors, or others) are likely to be most important in colorectal cancer development?
  4. For the most likely mechanisms of action involving alcohol and the development of colorectal cancer, how might other factors modify the effect of alcohol on colorectal cancer (for example, age, latency of effect, intensity, duration, and recency of exposure, presence of co-carcinogens, presence of threshold effect)? Do the causal mechanisms vary by cell type or other tumor characteristics?

To address these Key Questions we searched electronic databases for information on ethanol consumption and the possible risks for breast and colorectal cancers. Thirty-five breast cancer studies (five in humans, 15 in animals, and 15 in cell lines) and 31 colorectal cancer studies (one in humans, 19 in animals, 10 in cell lines, and one combination [animal and cell lines]) were included in the report. Information on study design and conduct was used to judge individual study internal validity. Data on experimental model, mechanism(s) examined, amount and duration of ethanol exposure, cancer formation, and intermediate outcomes were abstracted and tabled for review and discussion.

Evidence for Alcohol Consumption and Cancer Risk: Understanding Possible Mechanisms for Breast and Colorectal Cancers

Breast Cancer Studies

Human studies. We included five studies to evaluate the possible mechanisms for alcohol consumption and breast cancer risk: the first study examined effects of alcohol on estradiol, estrone, estrone sulfate, testosterone, androstenedione, progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and androstenediol; the second study examined the effects of alcohol on plasma and urinary hormone concentrations in premenopausal women; a third study examined the effect of alcohol on prolactin levels in menopausal women using estradiol replacement; a fourth study examined the effects of alcohol on estrogen levels in postmenopausal women; and a fifth study examined the relationship of alcohol consumption with antioxidant nutrients and biomarkers of oxidative stress. Although none of these five studies reported direct evidence of cancer, we included them given that alcohol was administered to assess possible hormonal mechanism(s) and biomarkers of oxidative stress.

Animal studies. We included 15 studies using animal models to evaluate the possible mechanisms for alcohol consumption and breast cancer risk. Outcomes measured varied across studies. Of the 15 included studies, 14 reported on the type of mechanism(s) examined and one did not. The type of mechanisms examined in the 14 studies included elevated levels of estrogen and or progesterone, biotransformation to acetaldehyde, formation of deoxyribonucleic acid (DNA) adducts, elevation of serum prolactin, suppression of cellular immunity, enhancement of rate of tumor progression, and effect on DNA synthesis. Administration and duration of ethanol exposure varied across all studies. Studies also varied on whether a carcinogen was administered to induce carcinogenesis. Of the 15 studies, 10 reported the use of a carcinogen to induce cancer:

  • dimethylene (a) anthracene [DMBA] (five studies)
  • N-methyl-N-nitrosurea [MNU] (two studies)
  • N-nitrosodimethylamine [NMDA] and 4-methylnitrosoamino-1-3-pyridyl-1-butanone [NNK] (one study)
  • MADB106 [one study]
  • bittner virus [one study].

Cell line studies. We included 15 studies using cell lines to evaluate the possible mechanisms for alcohol consumption and breast cancer risk. Twelve studies administered ethanol alone, and two studies administered ethanol combined with acetaldehyde. Cell lines examined in the studies included:

  • MCF-7 (six studies)
  • MCF-10F (two studies)
  • T4TD (one study)
  • MM46 tumor cells (one study)
  • MCF-7 + T47D (one study)
  • MCF-7 + T84 (one study)
  • MDA-MB-453 (one study)
  • MCF-7 + T47D + MDA-MB-231 (one study)
  • MCF-7 +ZR75.1 + BT-20 + MDA-MB-231 (one study).

Various mechanisms were reported by these studies: hormonal-related, DNA-adduct formation, inflammation and cell death, cell differentiation, increase cyclic adenosine monophosphate (cAMP), change in potassium channels, and modulation of gene expression.

Colorectal cancer studies.

Human study. We included one study using human tissues to evaluate the possible mechanism for alcohol consumption and colorectal cancer risk. The study exposed colonic mucosa to acetaldehyde vapor. Although the study did not report direct evidence to show causation of cancer, the authors concluded that acetaldehyde may cause an increase in risk of colon cancer via loss of cell-cell adhesion.

Animal studies. We included 19 studies using animal models to evaluate the possible mechanisms for alcohol consumption and colorectal cancer risk. Outcomes varied across all studies. Of the 19 included studies, 17 reported on the type of mechanism(s) examined and two did not. The type of mechanisms examined in the 17 studies included:

  • cytochrome system expression
  • generation of acetaldehyde
  • DNA methylation
  • effect of folate metabolism
  • cell proliferation
  • formation of acetaldehyde by human colonic bacteria
  • local mucosal effect
  • effect on various phases of carcinogenesis.

Administration and duration of ethanol exposure varied across all animal studies. Studies also varied on whether a carcinogen was administered to induce carcinogenesis. Of the 19 studies, 12 reported the use of a carcinogen to induce cancer:

  • 1,1-dimethylhydrazine (DMH) (six studies)
  • methylazoxymethanol (MAM) acetate (one study)
  • acetoxymethyl-methylnitrosamine (AMMN) (one study)
  • AMMN + cyanamide (CY) (one study)
  • azoxymethane (AOM) (three studies).

Cell line studies. We included 10 studies using cell lines to evaluate the possible mechanisms for alcohol consumption and colorectal cancer risk. Cell lines examined in the studies included:

  • Caco-2 (six studies)
  • HT-29 (one study)
  • colonic mucosa cells (one study)
  • Caco-2 + HT-29 (one study)
  • HT-29 + SW-1116 + HCT-15 (one study).

Various mechanisms were reported by these studies:

  • folate uptake modulation
  • tumor necrosis factor modulation
  • inflammation and cell death
  • formation of crosslinks with DNA
  • cell differentiation
  • modulation of gene expression.

Amount and duration of ethanol and/or acetaldehyde varied across all studies. Seven studies administered ethanol alone, while three studies administered ethanol combined with acetaldehyde.

Combination study (animal, cell line). We included one study that used a combination of animal (mice) and cell line (Caco-2) to evaluate the possible mechanisms for alcohol consumption and colorectal cancer risk. Intestinal cell proliferation as a result of phosphatidylethanol accumulation was the examined mechanism. The animal study administered ethanol, and the cell line study administered either ethanol or acetaldehyde. The primary outcome reported was disruption of cellular signals.

Discussion

The relationship between alcohol consumption and the risk of breast and colorectal cancers has been assessed in several systematic reviews and epidemiology studies (cohort and case-control studies). In this report, we looked at the potential mechanism(s) connecting both breast and colorectal cancers with alcohol consumption, under the assumption that there is a causal relationship. Our report did not focus on such a causal relationship reported in epidemiology literature where alcohol consumption was not under experimental control, but rather on potential mechanism(s) in studies that administered either alcohol or acetaldehyde in the absence of cancer. Only the human studies that actually administered ethanol regardless of experimental model were abstracted and included in the primary evidence base to assess possible mechanism(s). In addition, given that acetaldehyde is a metabolite of ethanol, we included animal studies that administered either alcohol and/or acetaldehyde in our evidence base. In humans, acetaldehyde levels in the blood are either very low or undetectable following alcohol consumption. Epidemiology studies that administered survey questionnaires to assess alcohol consumption and cancer risk and hypothesis-generating studies that examined potential pathways connecting alcohol to cancer risk were included as a separate evidence base.

The majority of the animal studies that chemically induced tumors through the administration of both alcohol and a carcinogen reported an increase in the carcinogenic effect; however, these studies can only offer indirect evidence of a connection between alcohol consumption and increased cancer risk in humans. Most of these studies varied in terms of quantity of ethanol and timing of administration relative to the carcinogen that was used in the study to induce carcinogenesis. Though some of the possible mechanisms identified in this report have been evaluated in a variety of experimental models (i.e., human, animals, cell lines), others have simply been examined as hypothesis generating and as such may call for future research.

Breast cancer. Both human and animal studies included in our primary evidence base point to a connection between alcohol intake and changes in blood hormone levels, especially elevated levels of estrogen and androgens in humans. Several cell line studies also suggest that estrogen receptor pathways may be altered by ethanol. Increased estrogen levels may increase the risk of breast cancer through increases in cell proliferation and alterations in estrogen receptors. Elevation in prolactin levels were also examined in human and animal studies. While not as extensive as the estrogen-related studies, these studies give some indication that alcohol consumption may alter prolactin levels and increase the risk of developing breast cancer. In order to report the role of oxidative stress in breast cancer, one human study measured changes in the levels of serum biomarkers.

The formation of acetaldehyde after ethanol consumption and its involvement in breast cancer has been examined in human epidemiology studies of enzyme polymorphism. Polymorphism in the enzymes that metabolize ethanol may increase an individual’s exposure to toxic metabolites such as acetaldehyde and influence cancer risk if acetaldehyde is involved in breast cancer development. In animal studies, conversion of ethanol to acetaldehyde in mammary tissue has been reported to have a significant effect on the progression of tumor development. Events downstream from acetaldehyde are likely being altered by the presence of acetaldehyde and may lead to enhanced tumor development.

Enhancement of cell proliferation and tumor progression related to ethanol consumption and conversion to acetaldehyde were examined in animal and cell line studies. The findings of these studies suggest that alterations in cell proliferation due to alcohol exposure may be a possible mechanism increasing breast cancer risk.

Colorectal cancer. One human study reported that acetaldehyde disrupts epithelial tight junctions and cell adhesion. Several animal studies also looked at the effects of acetaldehyde in the colon and reported the following: mucosal damage after ethanol consumption, increased degradation of folate, stimulation of rectal carcinogenesis, and an increased effect of carcinogens in the presence of acetaldehyde. In cell line studies, acetaldehyde exposure was reported to influence the initial steps of colonic carcinogenesis and later tumor development and decrease the activity of some brush border enzymes. Finally, a study using human tissue, animal tissue, and a cell line found evidence that acetaldehyde stimulates cell proliferation in intestinal crypt cells and therefore acetaldehyde may act as a cocarcinogen in the colon. These studies (human, animal, and cell line) combine to suggest that acetaldehyde production in the colon may provide a potential causal mechanism by which alcohol contributes to the development of colon cancer.

An effect of ethanol consumption on cell proliferation in the colon was investigated in a combination study (animal and cell line). In this study, chronic alcohol exposure resulted in disruption of signals that normally restrict proliferation in highly confluent intestinal cells, thereby facilitating abnormal intestinal proliferation. Several animal studies reported enhanced growth of mucosal tissue after chronic ethanol consumption. Cell studies indicate that exposure to ethanol and acetaldehyde increases cell proliferation and damages DNA which may contribute to cancer development. Together these studies suggest that ethanol and acetaldehyde exposure in the colorectal mucosa may increase cell proliferation and be a potential mechanism connecting alcohol consumption to colorectal cancer risk.

Conclusions

Based on our systematic review of the literature, many potential mechanisms by which alcohol may influence the development of breast or colorectal cancers have been explored but the exact connection or connections remain unclear. The evidence points in several directions but the importance of any one mechanism is not apparent at this time. Several mechanisms have been proposed and human, animal, and cell line studies have provided evidence in support of several mechanisms, but the findings have been inconsistent. The diversity of experimental protocols among the studies included in this report could have contributed to the lack of consistency. Furthermore, variation across included studies for both the route of administration and amount of ethanol may have influenced results. Based on animal studies alone, researchers may be inclined to infer a causal link between alcohol and the risk of breast or colorectal cancers. In addition, although a majority of the epidemiology studies reported that alcohol increased the risk of both breast and colorectal cancers, we cannot discount uncontrolled confounding by diet and related lifestyles.