title: SERMs attenuate estrogen-induced malignant transformation of human mammary epithelial cells by upregulating detoxification of oxidative metabolites.
abstract: The risk of developing hormone-dependent cancers with long-term exposure to estrogens is attributed both to proliferative, hormonal actions at the estrogen receptor (ER) and to chemical carcinogenesis elicited by genotoxic, oxidative estrogen metabolites. Nontumorigenic MCF-10A human breast epithelial cells are classified as ER(-) and undergo estrogen-induced malignant transformation. Selective estrogen receptor modulators (SERM), in use for breast cancer chemoprevention and for postmenopausal osteoporosis, were observed to inhibit malignant transformation, as measured by anchorage-independent colony growth. This chemopreventive activity was observed to correlate with reduced levels of oxidative estrogen metabolites, cellular reactive oxygen species (ROS), and DNA oxidation. The ability of raloxifene, desmethylarzoxifene (DMA), and bazedoxifene to inhibit this chemical carcinogenesis pathway was not shared by 4-hydroxytamoxifen. Regulation of phase II rather than phase I metabolic enzymes was implicated mechanistically: raloxifene and DMA were observed to upregulate sulfotransferase (SULT 1E1) and glucuronidase (UGT 1A1). The results support upregulation of phase II metabolism in detoxification of catechol estrogen metabolites leading to attenuated ROS formation as a mechanism for inhibition of malignant transformation by a subset of clinically important SERMs.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street, Chicago, IL 60612. thatcher@uic.edu.
authors.forename: L P Madhubhani P
authors.initials: LP
authors.lastname: Hemachandra
authors.forename: Hitisha
authors.initials: H
authors.lastname: Patel
authors.forename: R Esala P
authors.initials: RE
authors.lastname: Chandrasena
authors.forename: Jaewoo
authors.initials: J
authors.lastname: Choi
authors.forename: Sujeewa C
authors.initials: SC
authors.lastname: Piyankarage
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.forename: Yijin
authors.initials: Y
authors.lastname: Wang
authors.forename: Emily N
authors.initials: EN
authors.lastname: Thayer
authors.forename: Robert A
authors.initials: RA
authors.lastname: Scism
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Michalsen
authors.forename: Rui
authors.initials: R
authors.lastname: Xiong
authors.forename: Marton I
authors.initials: MI
authors.lastname: Siklos
authors.forename: Judy L
authors.initials: JL
authors.lastname: Bolton
authors.forename: Gregory R J
authors.initials: GR
authors.lastname: Thatcher
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects*; D004958:Estradiol / Q000009:adverse effects*; D006801:Humans; D008658:Inactivation, Metabolic / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology; D061986:MCF-7 Cells; D042361:Mammary Glands, Human / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016877:Oxidants / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D007211:Indoles; D016877:Oxidants; D010880:Piperidines; D017382:Reactive Oxygen Species; D020845:Selective Estrogen Receptor Modulators; D013876:Thiophenes; C571169:desmethylarzoxifene; D013629:Tamoxifen; C016601:afimoxifene; D020849:Raloxifene Hydrochloride; D004958:Estradiol; C447119:bazedoxifene