Oxidative stress shapes breast cancer phenotype through chronic activation of ATM-dependent signaling

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dc.contributor.authorAlpay, M.
dc.contributor.authorBackman, L.R.F.
dc.contributor.authorCheng, X.
dc.contributor.authorDukel, M.
dc.contributor.authorKim, W.J.
dc.contributor.authorAi, L.
dc.contributor.authorBrown, K.D.
dc.date.accessioned2020-04-30T13:33:02Z
dc.date.available2020-04-30T13:33:02Z
dc.date.issued2015
dc.departmentDÜ, Tıp Fakültesi, Temel Tıp Bilimleri Bölümüen_US
dc.descriptionPubMed ID: 25862169en_US
dc.description.abstractReactive oxygen species (ROS) are thought to be among the initiating insults that drive carcinogenesis; however, beyond the mutagenic properties of ROS, it is unclear how reactive oxygen species and response to redox imbalance may shape cancer phenotype. We have previously observed that basal activity of the powerfully oncogenic transcription factor NF-?B in cultured breast cancer and other tumor cell lines is dependent upon the DNA damage-responsive kinase ATM. Here we show that, in MDA-MB-231 and HeLa cells, basal ATM-dependent NF-?B activation occurs through a canonical DNA damage-responsive signaling pathway as knockdown of two proteins involved in this signaling pathway, ERC1 and TAB1, results in loss of NF-?B basal activity. We further show that knockdown of ATM in MDA-MB-231, a breast cancer line with a pronounced mesenchymal phenotype, results in the reversion of these cells to an epithelial morphology and gene expression pattern. Culture of MDA-MB-231 and HeLa cells on the antioxidant N-acetyl cysteine (NAC) blunted NF-?B transcriptional activity, and long-term culture on low doses of NAC resulted in coordinate reductions in steady-state ROS levels, acquisition of an epithelial morphology, as well as upregulation of epithelial and downregulation of mesenchymal marker gene expression. Moreover, these reversible effects are attributable, at least in part, to downregulation of ATM-dependent NF-?B signaling in MDA-MB-231 cells as RNAi-mediated knockdown of the NF-?B subunit RelA or its upstream activator TG2 produced similar alterations in phenotype. We conclude that chronic activation of ATM in response to persistent ROS insult triggers continual activation of the oncogenic NF-?B transcriptional complex that, in turn, promotes aggressive breast cancer phenotype. © 2015, Springer Science+Business Media New York.en_US
dc.description.sponsorshipNational Institutes of Health: R03 CA125824en_US
dc.identifier.doi10.1007/s10549-015-3368-5en_US
dc.identifier.endpage87en_US
dc.identifier.issn0167-6806
dc.identifier.issue1en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage75en_US
dc.identifier.urihttps://dx.doi.org/10.1007/s10549-015-3368-5
dc.identifier.urihttps://hdl.handle.net/20.500.12684/522
dc.identifier.volume151en_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherSpringer New York LLCen_US
dc.relation.ispartofBreast Cancer Research and Treatmenten_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectGene expression; Mesenchymal-to-epithelial transition; Oxidative stress; Signalingen_US
dc.titleOxidative stress shapes breast cancer phenotype through chronic activation of ATM-dependent signalingen_US
dc.typeArticleen_US

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