Expression of UGT2B7, a UDP-glucuronosyltransferase implicated in the metabolism of 4-hydroxyestrone and all-trans retinoic acid, in normal human breast parenchyma and in invasive and in situ breast cancers.
Glucuronidation, mediated by UDP-glucuronosyltransferases (UGTs), affects the actions and disposition of diverse endo- and xenobiotics. In the case of catecholestrogens (CEs), glucuronidation is likely to block their oxidation to quinone estrogens that are the putative mediators of CEs' actions as initiators of cancers. The goal of this study was to determine whether UGT2B7, the isoenzyme with a high affinity for 4-hydroxyestrone, is expressed in human breast parenchyma. Glucuronidation of 4-hydroxyestrone has relevance to breast carcinogenesis because quinone metabolites of 4-hydroxylated CEs can form potentially mutagenic depurinating DNA adducts, and because in breast tissue estrone is likely to be the predominant estrogen available for 4-hydroxylation. Using reverse transcriptase-polymerase chain reaction, immunocytochemistry, immunoblot analyses, and assays of glucuronidation of 4-hydroxyestrone, we show that UGT2B7 is expressed in human mammary epithelium, and that its expression is dramatically reduced in invasive breast cancers. In many in situ carcinomas, however, 4-hydroxyestrone immunostaining was not only preserved but even more intense than in normal mammary epithelium. The finding of reduced UGT2B7 protein and glucuronidation of 4-hydroxyestrone in invasive cancers suggests a tumor-suppressor function for the enzyme. Recent identification of all-trans retinoic acid as a substrate of UGT2B7 suggests that this function includes the generation of retinoyl-beta-glucuronide, a potent mediator of actions of retinoids important for maintaining epithelia in a differentiated state. Current knowledge does not provide any ready explanation for the apparent increase in UGT2B7 expression in carcinomas in situ. However, this finding, together with reduced immunostaining at loci showing breach of the basement membrane (microinvasion), suggests involvement of UGT2B7-catalyzed reaction(s) in protection against invasion of surrounding tissue by cancer cells.
Gestl
Shelley A
SA
Departments of Obstetrics andGynecology andPathology, Pennsylvania State UniversityCollege of Medicine, Hershey, Pennsylvania.
Green
Mitchell D
MD
Shearer
Debra A
DA
Frauenhoffer
Elizabeth
E
Tephly
Thomas R
TR
Weisz
Judith
J
D001940:Breast / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006894:Hydroxyestrones / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000378:metabolism; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution; D014212:Tretinoin / Q000378:metabolism*
D006894:Hydroxyestrones; D012333:RNA, Messenger; C026418:4-hydroxyestrone; D014212:Tretinoin; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase