The relationship between alcohol metabolism, estrogen levels, and breast cancer risk.

Many epidemiological studies have demonstrated a positive association between alcohol consumption and an increased risk for breast cancer (for a recent review, see Hamajima et al. 2002). These studies have shown that even moderate alcohol consumption leads to a significantly increased risk for breast cancer. Moreover, Longnecker (1994) calculated that approximately 4 percent of newly diagnosed cases of breast cancer in the United States result from chronic alcohol intake. Although the exact mechanisms through which alcohol exerts its cocarcinogenic effect on the breast remain unknown, a genetic predisposition may play an important role. This predisposition could involve the enzyme alcohol dehydrogenase (ADH), which breaks down alcohol to acetaldehyde. Recent studies have shown that people who carry genes encoding highly active ADH enzymes leading to elevated acetaldehyde levels are at particularly high risk for a variety of cancers, including breast cancer. ADH Variants and Breast Cancer Risk As described in more detail in the accompanying article "Alcohol Metabolism and Cancer Risk," there are seven types of ADH that are encoded by different genes. Moreover, two of the seven ADH genes, called ADH1B and ADH1C, are polymorphic-that is, they exist in more than one variant (i.e., allele). The enzymes encoded by these alleles differ in their activity and therefore result in the accumulation of different quantities of acetaldehyde. In Caucasians, polymorphism of the ADH1C gene is particularly relevant to cancer risk. This gene has two known alleles: a highly active allele called ADH1C*1 and a less active allele called ADH1C*2. Several case-control studies1 have assessed the relationship between the active ADH1C*1 allele (and, thus, elevated acetaldehyde levels) and the risk of breast cancer. Of these, three studies concluded that the ADH1C*1 allele plays a role in breast cancer development, particularly in women who have not yet entered menopause (i.e., are premenopausal); conversely, one study did not find such a positive correlation. Freudenheim and colleagues (1999) compared 315 breast cancer patients and 356 age-matched control subjects. Among premenopausal (but not postmenopausal) women, the researchers found that breast cancer risk was higher in women carrying two copies of the ADH1C*1 allele (i.e., homozygous for ADH1C*1) compared with women carrying only one or no copy of the ADH1C*1 allele (i.e., heterozygous or homozygous for the ADH1C*2 allele). Moreover, premenopausal women who were homozygous for ADH1C*1 and had a higher level of alcohol intake2 were at greater risk of breast cancer than were comparable women with moderate alcohol intake (odds ratio 3.6, 95% CI 1.5-8.8). More recently, Terry and colleagues (2006) compared more than 1,000 breast cancer patients with more than 1,100 control subjects. These researchers found that among women homozygous for ADH1C*1, a lifetime consumption of 15 to 30 g alcohol per day (which corresponds to approximately one to two drinks per day) was associated with a two-fold increase in breast cancer risk (95% CI 1.1-3.5). However, this increase in risk was not seen in women with the same alcohol consumption who were heterozygous or homozygous for ADH1C*2. Again, the increase in risk was particularly pronounced among premenopausal women. In a European study, Coutelle and colleagues (2004) reported that the ADH1C*1 allele was significantly more common in moderate alcohol consumers with breast cancer than in age-matched control subjects without cancer. Furthermore, women homozygous for ADH1C*1 had a 1.8-times greater risk of breast cancer than women with other allele combinations (95% CI 1.4-2.3). In contrast to these three studies, Hines and colleagues (2000), who evaluated 465 breast cancer patients and 621 control subjects participating in the Nurses' Health Study, did not find any effect of ADH1C polymorphism on breast cancer risk. However, this study included women with relatively low weekly alcohol consumption, which may not result in sufficiently high acetaldehyde concentrations. …