Estrogen-Mediated Breast Carcinogenesis: The Role of Sulfation Pharmacogenetics
Abstract
The metabolites of estrogens, the catecholestrogens (CEs), can be activated to form stable and depurinating DNA adducts through a series of reactions. The adducts formed from these CEs, namely 4-hydroxyestrone (4-OHE1) and 4-hydroxyestradiol (4-OHE2), result in mutations that lead to genotoxicity and therefore breast carcinogenesis. Prevention of the genotoxic effects can be achieved in part through the sulfate-conjugation of the CEs, catalyzed by sulfotransferase (SULT) enzymes. Because many of the human SULTs are genetically polymorphic, inherited differences in activities of these enzymes may contribute to the pathophysiology of breast cancer. We determined the activity of 13 recombinant human SULTs with 4-OHE1, 4-OHE2, 2-hydroxyestrone (2-OHE1) 2-hydroxyestradiol (2-OHE2) , estrone (E1) and 17-Beta estradiol (E2). SULT1E1 had the highest affinity for them all, with apparent Km values of 0.31 and 0.18 Micro-M for 4-OHE1 and 4-CHE2. We also performed immunohistochemical studies with SULT1E1 antibody and determined the presence of SULT1E1 in breast tissue block arrays of non-cancer and tumor samples. We then reseguenced the SULT1E1 gene with DNA from 60 Caucasians and 60 African-American subjects and identified 3 nonsynonymous cSNPs that changed encoded amino acids: A5p22Tyr, Ala32Val and Pro253His. Functional genomics studies showed that 2 of the 3 nonsynonymous cSNPs had decreased enzyme activities with corresponding decreases in immunoreactive protein. These observations suggest that ethnic-specific variations in sulfation of CEs catalyzed by SULT1E1 may contribute variable risk to the development and pathophysiology of estrogen-dependent diseases such as breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2002
- Accession Number
- ADB282253
Entities
People
- Araba Adjei