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Permanent link (DOI): https://doi.org/10.7939/R3DF6KH1K

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Oxidative stress mediates estrogen receptor independent killing and contributes to tamoxifen resistance Open Access

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Author or creator
Bekele, Raie T.
Venkatraman, Ganesh
Liu, Rong-Zong
Tang, Xiaoyun
Mi, Si
Benesch, Matthew
Mackey, John R.
Godbout, Roseline
Curtis, Jonathan M.
McMullen, Todd
Brindley, David N.
Additional contributors
Subject/Keyword
Ceramide
Activation
NRF2
Protein-Kinase-C
Estrogen-Receptor-Beta
P-Glycoprotein
Gene-Expression
Tumor-Growth
Inhibition
Induced Apoptosis
Type of item
Journal Article (Published)
Language
English
Place
Time
Description
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.
Date created
2016
DOI
doi:10.7939/R3DF6KH1K
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Attribution 4.0 International
Citation for previous publication
Bekele, Raie T., Venkatraman, Ganesh, Liu, Rong-Zong, Tang, Xiaoyun, Mi, Si, Benesch, Matthew, Mackey, John R., Godbout, Roseline, Curtis, Jonathan M., McMullen, Todd, & Brindley, David N. (2016). Oxidative stress mediates estrogen receptor independent killing and contributes to tamoxifen resistance. Scientific Reports, 6, [17].  http://dx.doi.org/10.1038/srep21164

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File format: pdf (Portable Document Format)
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File size: 2283965
Last modified: 2017:09:06 16:44:46-06:00
Filename: SR_6_21164.pdf
Original checksum: 2a1319e78a096d0b79dd04cd77e47c41
Copyright note: © 2016 Nature Publishing Group
File title: Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: implications for tamoxifen therapy and resistance
File author: Raie T. Bekele
Page count: 17
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