SULT1A1 and UGT1A1 polymorphisms are associated with breast cancer phenotypes in women

Abstract

Estrogens are an important factor in the development and treatment of breast cancer. SULT1A1 and UGT1A1 metabolize estrogen agonists and antagonists and thus may influence breast cancer risk and treatment. SULT1A1 and UGT1A1 are genetically polymorphic. A common SULT1A1 allele is defined by a His213Arg amino acid substitution (*2) and results in an enzyme with low activity. A common UGT1A1 polymorphism is defined by TA repeats (5,6,7 or 8) in the promoter TATA-box. Transcriptional activity of the promoter is inversely proportional to the number of TA repeats. We hypothesized that individuals with variant capacity to metabolize estrogen agonists and antagonists would exhibit different tumor phenotypes. We performed a case-series study in a cohort of 190 Caucasian women with breast cancer. SULT1A1 and UGT1A1 genotypes were determined using Pyrosequencing and Genescan techniques, respectively, and genotype-phenotype associations were analyzed. We found that SULT1A1*1/*1 genotype was associated with a tumor size <2 cm (OR=2.5, P=0.03). UGT1A1 genotypes containing only low activity alleles (*28/*28, *34/*34 or *28/*34) were associated with late (≥60 years) age of onset (OR=3.2, P=0.049) and DCIS (OR=5.7, P=0.02). Presence of UGT1A1*28 or/and *34 was associated with tumor size ≤4 cm (OR=0.1, P=0.004). In summary, genetic polymorphisms affecting the sulfation and glucuronidation of estrogen agonists and antagonists appear to be associated with specific tumor characteristics. Clinical Pharmacology & Therapeutics (2004) 75, P1–P1; doi: 10.1016/j.clpt.2003.11.004