Risk factors in alcohol associated breast cancer: alcohol dehydrogenase polymorphism and estrogens.
Chronic alcohol consumption is associated with an increased risk for breast cancer, even if consumed in moderate doses. Since acetaldehyde is a carcinogenic factor associated with chronic alcohol consumption, individuals with the alcohol dehydrogenase 1C*1 allele (ADH1C*1 allele) seem to be at particular risk, since this allele encodes for a rapidly ethanol metabolizing enzyme leading to increased acetaldehyde levels. Since recent epidemiological studies demonstrated an increased risk for breast cancer for individuals with the ADH1C*1 allele, we have investigated here ADH1C genotypes in moderate alcohol consumers. Furthermore, estradiols are also known risk factors for breast cancer and acute alcohol ingestion in high doses results in increased serum estradiol concentrations. Thus, in the present study, we tested the effect of low ethanol doses on estrogen serum concentrations. We analyzed the ADH1C genotype in 117 moderate alcohol consumers with breast cancer and in 111 age-matched women with alcohol associated diseases without cancer (74 cirrhotics, 22 patients with pancreatitis and 15 alcohol dependent patients). In addition, 107 healthy controls were studied. Genotyping of the ADH1C-locus was performed using polymerase chain reaction-based restriction fragment length polymorphism methods on leukocyte DNA. To study the effects of ethanol on estradiol levels, ethanol in a dose of 0.225 g/kg body weight was given orally to 8 premenopausal women at various time points of their menstrual cycle. Thereafter estradiol serum concentrations were measured over time. The allele frequency of the ADH1C*1 allele was found to be significantly increased in moderate alcohol consumers with breast cancer as compared to age-matched alcoholic controls without cancer (62% vs. 41.9%, p=0.0035). Women with the ADH1C*1,1 genotype were found to be 1.8 times more at risk for breast cancer than those with another genotype (95% CI 1.431-2.330, p<0.001). Oral ethanol increased serum estradiol levels significantly by 27-38%. The data demonstrate that moderate alcohol consumers with the ADH1C*1 allele have an increased risk to develop breast cancer and even small amounts of alcohol increase serum estradiol levels significantly in premenopausal women especially in the midphase of the menstrual cycle.
Coutelle
C
C
Department of Medicine and Laboratory of Alcohol Research, Liver Disease and Nutrition, Salem Medical Centre, Heidelberg, Germany.
Höhn
B
B
Benesova
M
M
Oneta
C M
CM
Quattrochi
P
P
Roth
H-J
HJ
Schmidt-Gayk
H
H
Schneeweiss
A
A
Bastert
G
G
Seitz
H K
HK
D000328:Adult; D000368:Aged; D000426:Alcohol Dehydrogenase / Q000235:genetics*; D001943:Breast Neoplasms / Q000209:etiology* / Q000235:genetics*; D004958:Estradiol / Q000097:blood*; D000431:Ethanol / Q000009:adverse effects*; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017697:Premenopause / Q000097:blood; D012307:Risk Factors
D000431:Ethanol; D004958:Estradiol; C420272:ADH1C protein, human; D000426:Alcohol Dehydrogenase