Estrogen-Mediated Breast Carcinogenesis: The Role of Sulfation Pharmacogenetics
Abstract
Catecholestrogens (CEs) are activated to form stable and depurinating DNA adducts. Adducts formed from 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. Many of the human SULTs are genetically polymorphic, thus, 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 Mu-M for 4-OHE1 and 4-OHE2. Immunohistochemical studies with SULT1E1 antibody on breast tissue block arrays of non-cancer and tumor samples, detected SULT1E1 enzyme protein. Resequencing of SULT1E1 from DNA of 60 Caucasians and 60 African-Americans identified 3 SNPs which changed encoded amino acids: Asp22Tyr, Ala32Val and Pro253His. The corresponding enzyme activity levels ranged from 26 to 69 and to 315% of the wild type respectively. Thus, variations in sulfation of CEs catalyzed by SULTs, may confer variable risks to the development of breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2001
- Accession Number
- ADB268484
Entities
People
- Araba Adjei