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10.18632/oncotarget.10516

http://scihub22266oqcxt.onion/10.18632/oncotarget.10516
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C5352084!5352084 !27438141
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suck abstract from ncbi


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pmid27438141
      Oncotarget 2017 ; 8 (1 ): 164-178
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  • 4-Hydroxyestradiol induces mammary epithelial cell transformation through Nrf2-mediated heme oxygenase-1 overexpression #MMPMID27438141
  • Park SA ; Lee MH ; Na HK ; Surh YJ
  • Oncotarget 2017[Jan]; 8 (1 ): 164-178 PMID27438141 show ga
  • Estrogen (17?-estradiol, E2) undergoes oxidative metabolism by CYP1B1 to form 4-hydroxyestradiol (4-OHE2), a putative carcinogenic metabolite of estrogen. Our previous study showed that 4-OHE2-induced production of reactive oxygen species contributed to neoplastic transformation of human breast epithelial (MCF-10A) cells. In this study, 4-OHE2, but not E2, increased the expression of heme oxygenase-1 (HO-1), a sensor and regulator of oxidative stress, in MCF-10A cells. Silencing the HO-1 gene in MCF-10A cells suppressed 4-OHE2-induced cell proliferation and transformation. In addition, subcutaneous administration of 4-OHE2 markedly enhanced the growth of the MDA-MB-231 human breast cancer xenografts, which was retarded by zinc protoporphyrin, a pharmacological inhibitor of HO-1. 4-OHE2-induced HO-1 expression was mediated by NF-E2-related factor 2 (Nrf2). We speculate that an electrophilic quinone formed as a consequence of oxidation of 4-OHE2 binds directly to Kelch-like ECH-associated protein 1 (Keap1), an inhibitory protein that sequesters Nrf2 in the cytoplasm. This will diminish association between Nrf2 and Keap1. 4-OHE2 failed to interrupt the interaction between Keap1 and Nrf2 and to induce HO-1 expression in Keap1-C273S or C288S mutant cells. Lano-LC-ESI-MS/MS analysis in MCF-10A-Keap1-WT cells which were treated with 4-OHE2 revealed that the peptide fragment containing Cys288 gained a molecular mass of 287.15 Da, equivalent to the addition of a single molecule of 4-OHE2-derived ortho-quinones.
  • |*Gene Expression [MESH]
  • |Animals [MESH]
  • |Breast Neoplasms/*etiology/*metabolism/pathology [MESH]
  • |Cell Line, Tumor [MESH]
  • |Cell Proliferation/drug effects [MESH]
  • |Cell Transformation, Neoplastic/*genetics/*metabolism [MESH]
  • |Disease Models, Animal [MESH]
  • |Epithelial Cells/drug effects/metabolism [MESH]
  • |Estrogens, Catechol/*adverse effects [MESH]
  • |Female [MESH]
  • |Gene Expression Regulation, Neoplastic [MESH]
  • |Heme Oxygenase-1/*genetics/metabolism [MESH]
  • |Heterografts [MESH]
  • |Humans [MESH]
  • |Mice [MESH]
  • |Mice, Knockout [MESH]
  • |NF-E2-Related Factor 2/genetics/*metabolism [MESH]
  • |Protein Binding [MESH]
  • |Response Elements [MESH]


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