Genetic polymorphisms in human SULT1A1 and UGT1A1 genes associate with breast tumor characteristics: a case-series study
1 Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
2 Department of Molecular Biology and Biotechnology, Russian State Medical University, Moscow, Russia
3 Department of Fetal and Maternal Medicine, Drexel Center for Genetics, Philadelphia, Pennsylvania, USA
4 Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
5 Department of Clinical Pharmacology, Merck & Co., Inc., Blue Bell, Pennsylvania, USA
Breast Cancer Research 2005, 7:R909-R921 doi:10.1186/bcr1318Published: 21 September 2005
Estrogens are important in breast cancer development. SULT1A1 and UGT1A1 catalyze estrogen metabolism and are polymorphic. The SULT1A1*2 protein exhibits low activity, and a TA repeat within the UGT1A1 promoter alters the level of expression of the protein. We hypothesized that the SULT1A1*2 allozyme has decreased capacity to sulfate estrogens, that the SULT1A1*2 allele conferred increased capacity of cells to proliferate in response to estrogens, and that individuals with the variant SULT1A1 and UGT1A1 genotypes exhibited different breast tumor characteristics.
The capacity for SULT1A1*2 to sulfate 17β-estradiol and the capacity for cells expressing SULT1A1*1 or SULT1A1*2 to proliferate in response to 17β-estradiol was evaluated. A case-series study was performed in a total of 210 women with incident breast cancer, including 177 Caucasians, 25 African-Americans and eight women of other ethnic background. The SULT1A1 and UGT1A1 genotypes were determined and a logistic regression model was used to analyze genotype–phenotype associations.
We determined that the SULT1A1*1/*1 high-activity genotype was associated with tumor size ≤2 cm (odds ratio = 2.63, 95% confidence interval = 1.25–5.56, P = 0.02). Individuals with low-activity UGT1A1 genotypes (UGT1A1*28/*28 or UGT1A1*28/*34) were more likely to have an age at diagnosis ≥60 years (odds ratio = 3.70, 95% confidence interval = 1.33–10.00, P = 0.01). Individuals with both SULT1A1 and UGT1A1 high-activity genotypes had low tumor grade (odds ratio = 2.56, 95% confidence interval = 1.04–6.25, P = 0.05). Upon stratification by estrogen receptor status, significant associations were observed predominantly in estrogen receptor-negative tumors.
The data suggest that genetic variation in SULT1A1 and UGT1A1 may influence breast cancer characteristics and might be important for breast cancer prognosis.