title: Relative involvement of three 17beta-hydroxysteroid dehydrogenases (types 1, 7 and 12) in the formation of estradiol in various breast cancer cell lines using selective inhibitors.
abstract: We investigated the relative involvement of three reductive 17beta-hydroxysteroid dehydrogenase (17beta-HSD) isoforms, namely types 1, 7 and 12, in the formation of potent estrogen estradiol (E2) in 10 human breast cancer cell lines (T-47D, MCF-7, ZR-75-1, CAMA-1, BT-20, BRC-17, BRC-31, BRC-32, BRC-36 and BRN-196) and also in 1 choriocarcinoma cell line (JEG-3) using selective inhibitors. In T-47D, BT-20 and JEG-3 cells, a 17beta-HSD1 inhibitor almost completely inhibited the formation of E2 at 1microM from 60nM of estrone (E1) (98%, 91% and 90%, respectively), whereas no significant inhibition of E2 formation was obtained using inhibitors of types 7 and 12. However, we obtained lower levels of inhibition (32%, 36% and 35% respectively using inhibitors of types 1, 7 and 12 at 10microM) in MCF-7 cells and even lower and variable levels of inhibition (15%, 23% and 18% respectively using inhibitors of types 1, 7 and 12 at 10microM) in ZR-75-1 cells. No inhibition of E2 formation was observed in CAMA-1 cells with a 17beta-HSD1 inhibitor at 1microM whereas inhibitors of types 7 and 12 inhibited 40% and 30% of E2 formation, respectively. In BRC and BRN cell lines, types 1, 7 and 12 17beta-HSDs were all involved in the formation of E2, but type 12 seemed to predominate. At 10microM, each inhibitor inhibited 10-50% of the formation of E2. Using MCF-7 and BRC-32 cell lines, a combination of the three inhibitors (3x10microM) does not fully inhibit the 17beta-HSD activity (65% and 75%). In addition to identify the relative importance of types 1, 7 and 12 17beta-HSDs in the formation of E2 in human breast cancer cell lines, our results show also a great variability between each cell line. In some cases the formation of E2 was completely inhibited, but this was not the result observed in other cell lines, suggesting the presence of another enzyme involved in the biosynthesis of E2.
authors.affiliation: Oncology and Molecular Endocrinology Laboratory (Medicinal Chemistry Division), CHUQ-CHUL Research Center and Université Laval, 2705 Laurier Boulevard, Québec, Québec G1V 4G2, Canada.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Laplante
authors.forename: Claudine
authors.initials: C
authors.lastname: Rancourt
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000145:classification / Q000378:metabolism*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004958:Estradiol / Q000096:biosynthesis* / Q000737:chemistry; D004970:Estrone / Q000737:chemistry / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D004970:Estrone; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase