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Oncology and Molecular Endocrinology Research Center, Laval University Medical Center (CHUL), Faculty of Pharmacy, Laval University, Quebec G1V 4G2, Canada [C. G.]; Department of Biology and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 [C. G., D. E. H.]; Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115 [I. D. V., S. E. H., D. J. H.]; Departments of Epidemiology [I. D. V., S. E. H., C. A. H., D. S., D. J. H.] and Nutrition [D. J. H.], Harvard School of Public Health, Boston, Massachusetts 02115; and Harvard Center for Cancer Prevention, Boston, Massachusetts 02115 [C. A. H., D. J. H.]
UDP-glucuronosyltransferases (UGTs) catalyze the detoxification and the elimination of a large number of endogenous and exogenous compounds in the liver and extrahepatic tissues. One of the UGT1A family members, UGT1A1, is involved in estradiol metabolism and, therefore, represents a candidate gene in breast carcinogenesis. A common insertion/deletion polymorphism in the TATA-box of the promoter region of UGT1A1 results in decreased initiation of transcription. In a previous study, we found a positive association between the UGT1A1 low-transcriptional alleles and premenopausal breast cancer risk in an African-American population. In the present study, we sought to determine whether the low-transcription UGT1A1 promoter allele, UGT1A1*28 [A(TA)7TAA], was associated with increased breast cancer risk among primarily Caucasian women in a nested case-control study within the Nurses’ Health Study cohort. No significant association between the UGT1A1*28 [A(TA)7TAA] allele and breast cancer was observed. Compared with women homozygous for the UGT1A1*1 [A(TA)6TAA] allele, the relative risk was 0.80 (confidence interval, 0.49–1.29) for women homozygous for the UGT1A1*28 allele. The effect of the UGT1A1 genotype on plasma hormone levels in postmenopausal women not using hormone replacement was also evaluated, and overall, no significant differences in hormone levels by genotypes were observed. When restricted to women who had at least one UGT1A1*28 allele and a body mass index at blood draw of >27 kg/m2, particularly in combination with the cytochrome p450c17
genotype, estrone and estradiol levels tended to vary by UGT1A1 genotypes. The results presented do not support a strong association between the UGT1A1 promoter polymorphism and the risk of breast cancer.
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