title: Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: implications for tamoxifen therapy and resistance.
abstract: Tamoxifen is the accepted therapy for patients with estrogen receptor-α (ERα)-positive breast cancer. However, clinical resistance to tamoxifen, as demonstrated by recurrence or progression on therapy, is frequent and precedes death from metastases. To improve breast cancer treatment it is vital to understand the mechanisms that result in tamoxifen resistance. This study shows that concentrations of tamoxifen and its metabolites, which accumulate in tumors of patients, killed both ERα-positive and ERα-negative breast cancer cells. This depended on oxidative damage and anti-oxidants rescued the cancer cells from tamoxifen-induced apoptosis. Breast cancer cells responded to tamoxifen-induced oxidation by increasing Nrf2 expression and subsequent activation of the anti-oxidant response element (ARE). This increased the transcription of anti-oxidant genes and multidrug resistance transporters. As a result, breast cancer cells are able to destroy or export toxic oxidation products leading to increased survival from tamoxifen-induced oxidative damage. These responses in cancer cells also occur in breast tumors of tamoxifen-treated mice. Additionally, high levels of expression of Nrf2, ABCC1, ABCC3 plus NAD(P)H dehydrogenase quinone-1 in breast tumors of patients at the time of diagnosis were prognostic of poor survival after tamoxifen therapy. Therefore, overcoming tamoxifen-induced activation of the ARE could increase the efficacy of tamoxifen in treating breast cancer.
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
authors.forename: Raie T
authors.initials: RT
authors.lastname: Bekele
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Venkatraman
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2, Canada.
authors.forename: Rong-Zong
authors.initials: RZ
authors.lastname: Liu
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Agricultural, Food and Nutritional Science (Lipid Chemistry Group), University of Alberta, Edmonton, Alberta, T6G 2P5, Canada.
authors.forename: Si
authors.initials: S
authors.lastname: Mi
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
authors.forename: Matthew G K
authors.initials: MG
authors.lastname: Benesch
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2, Canada.
authors.forename: John R
authors.initials: JR
authors.lastname: Mackey
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2, Canada.
authors.forename: Roseline
authors.initials: R
authors.lastname: Godbout
authors.affiliation: Department of Agricultural, Food and Nutritional Science (Lipid Chemistry Group), University of Alberta, Edmonton, Alberta, T6G 2P5, Canada.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Curtis
authors.affiliation: Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T6G 1Z2, Canada.|Department of Surgery, Walter C Mackenzie Health Science Centre, University of Alberta, Edmonton, T6G 2R7, Alberta, Canada.
authors.forename: Todd P W
authors.initials: TP
authors.lastname: McMullen
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
authors.forename: David N
authors.initials: DN
authors.lastname: Brindley
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D011379:Prognosis; D020218:Response Elements; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D000975:Antioxidants; D015415:Biomarkers; D002518:Ceramides; D047628:Estrogen Receptor alpha; D051267:NF-E2-Related Factor 2; D013629:Tamoxifen; D048031:JNK Mitogen-Activated Protein Kinases