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Selective Insensitivity of ZR-75-1 Human Breast Cancer Cells to 2-Methoxyestradiol: Evidence for Type II 17ß-Hydroxysteroid Dehydrogenase as the Underlying Cause

Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina

Requests for reprints: Bao Ting Zhu, Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Room 617, Coker Life Sciences Building, 700 Sumter Street, Columbia, SC 29208. Phone: 803-777-4802; Fax: 803-777-8356; E-mail: btzhu{at}cop.sc.edu.

2-Methoxyestradiol (2-MeO-E₂), a nonpolar endogenous metabolite of 17ß-estradiol, has strong antiproliferative, apoptotic, and antiangiogenic actions. Among the four human breast cancer cell lines tested (MCF-7, T-47D, ZR-75-1, and MDA-MB-435s), the ZR-75-1 cells were selectively insensitive to the antiproliferative actions of 2-MeO-E₂, although these cells had a similar sensitivity as other cell lines to several other anticancer agents (5-fluorouracil, mitomycin C, doxorubicin, colchicine, vinorelbine, and paclitaxel). Mechanistically, this insensitivity is largely attributable to the presence of high levels of a steroid-selective metabolizing enzyme, the type II 17ß-hydroxysteroid dehydrogenase (17ß-HSD), in the ZR-75-1 cells, which rapidly converts 2-MeO-E₂ to the inactive 2-methoxyestrone, but this enzyme does not metabolically inactivate other nonsteroidal anticancer agents. The type II 17ß-HSD–mediated conversion of 2-MeO-E₂ to 2-methoxyestrone in ZR-75-1 cells followed the first-order kinetics, with a very short half-life (2 hours). In comparison, the T-47D, MCF-7, and MDA-MB-435s human breast cancer cells, which were highly sensitive to 2-MeO-E₂, had very low or undetectable catalytic activity for the conversion of 2-MeO-E₂ to 2-methoxyestrone. Reverse transcription-PCR analysis of the mRNA levels of three known oxidative 17ß-HSD isozymes (types II, IV, and VIII) revealed that only the type II isozyme was selectively expressed in the ZR-75-1 cells, whereas the other two isozymes were expressed in all four cell lines. Taken together, our results showed, for the first time, that the high levels of type II 17ß-HSD present in ZR-75-1 cells were largely responsible for the facile conversion of 2-MeO-E₂ to 2-methoxyestrone and also for the selective insensitivity to the antiproliferative actions of 2-MeO-E₂.

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