Genetic polymorphisms in human SULT1A1 and UGT1A1 genes associate with breast tumor characteristics: a case-series study.
BACKGROUND
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.


METHODS
The capacity for SULT1A1*2 to sulfate 17beta-estradiol and the capacity for cells expressing SULT1A1*1 or SULT1A1*2 to proliferate in response to 17beta-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.


RESULTS
We determined that the SULT1A1*1/*1 high-activity genotype was associated with tumor size <or=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 >or=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.


CONCLUSIONS
The data suggest that genetic variation in SULT1A1 and UGT1A1 may influence breast cancer characteristics and might be important for breast cancer prognosis.
Shatalova
Ekaterina G
EG
Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA. ekaterina.shatalova@fccc.edu
Walther
Susan E
SE
Favorova
Olga O
OO
Rebbeck
Timothy R
TR
Blanchard
Rebecca L
RL
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015239:Arylsulfotransferase / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D004967:Estrogens / Q000378:metabolism; D005006:Ethnicity; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D011110:Polymorphism, Genetic; D011379:Prognosis; D011960:Receptors, Estrogen; D000099148:UGT1A1 Enzyme
D015239:Arylsulfotransferase; D004967:Estrogens; D014453:Glucuronosyltransferase; D011960:Receptors, Estrogen; D000099148:UGT1A1 Enzyme; C117544:SULT1A1 protein, human