title: Raloxifene and desmethylarzoxifene block estrogen-induced malignant transformation of human breast epithelial cells.
abstract: There is association between exposure to estrogens and the development and progression of hormone-dependent gynecological cancers. Chemical carcinogenesis by catechol estrogens derived from oxidative metabolism is thought to contribute to breast cancer, yet exact mechanisms remain elusive. Malignant transformation was studied in MCF-10A human mammary epithelial cells, since estrogens are not proliferative in this cell line. The human and equine estrogen components of estrogen replacement therapy (ERT) and their catechol metabolites were studied, along with the influence of co-administration of selective estrogen receptor modulators (SERMs), raloxifene and desmethyl-arzoxifene (DMA), and histone deacetylase inhibitors. Transformation was induced by human estrogens, and selectively by the 4-OH catechol metabolite, and to a lesser extent by an equine estrogen metabolite. The observed estrogen-induced upregulation of CYP450 1B1 in estrogen receptor negative MCF-10A cells, was compatible with a causal role for 4-OH catechol estrogens, as was attenuated transformation by CYP450 inhibitors. Estrogen-induced malignant transformation was blocked by SERMs correlating with a reduction in formation of nucleobase catechol estrogen (NCE) adducts and formation of 8-oxo-dG. NCE adducts can be formed consequent to DNA abasic site formation, but NCE adducts were also observed on incubation of estrogen quinones with free nucleotides. These results suggest that NCE adducts may be a biomarker for cellular electrophilic stress, which together with 8-oxo-dG as a biomarker of oxidative stress correlate with malignant transformation induced by estrogen oxidative metabolites. The observed attenuation of transformation by SERMs correlated with these biomarkers and may also be of clinical significance in breast cancer chemoprevention.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Illinois, USA.
authors.forename: Irida
authors.initials: I
authors.lastname: Kastrati
authors.forename: Praneeth D
authors.initials: PD
authors.lastname: Edirisinghe
authors.forename: L-P-Madhubani P
authors.initials: LP
authors.lastname: Hemachandra
authors.forename: Esala R
authors.initials: ER
authors.lastname: Chandrasena
authors.forename: Jaewoo
authors.initials: J
authors.lastname: Choi
authors.forename: Yue-Ting
authors.initials: YT
authors.lastname: Wang
authors.forename: Judy L
authors.initials: JL
authors.lastname: Bolton
authors.forename: Gregory R J
authors.initials: GR
authors.lastname: Thatcher
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001940:Breast / Q000473:pathology*; D002396:Catechols / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D004967:Estrogens / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006736:Horses; D006801:Humans; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D020849:Raloxifene Hydrochloride / Q000737:chemistry / Q000494:pharmacology*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D002396:Catechols; D018736:DNA Adducts; D004967:Estrogens; D056572:Histone Deacetylase Inhibitors; D010880:Piperidines; D020845:Selective Estrogen Receptor Modulators; D013876:Thiophenes; C571169:desmethylarzoxifene; C088015:benzothiophene; D020849:Raloxifene Hydrochloride; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003577:Cytochrome P-450 Enzyme System; C115121:LY 353381; D003849:Deoxyguanosine