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

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• 作者：Merve Alpay ; Lindsey R. F. Backman ; Xiaodong Cheng…
• 关键词：Oxidative stress ; Mesenchymal ; to ; epithelial transition ; Gene expression ; Signaling
• 刊名：Breast Cancer Research and Treatment
• 出版年：2015
• 出版时间：May 2015
• 年：2015
• 卷：151
• 期：1
• 页码：75-87
• 全文大小：1,162 KB
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• 作者单位：Merve Alpay (1) (3)
  Lindsey R. F. Backman (1)
  Xiaodong Cheng (2)
  Muzaffer Dukel (1)
  Wan-Ju Kim (1)
  Lingbao Ai (1)
  Kevin D. Brown (1)
  
  1. Dept of Biochemistry and Molecular Biology, University of Florida College of Medicine, Box 100245, Gainesville, FL, 32610, USA
  3. Duzce University Faculty of Medicine, Duzce, Turkey
  2. Dept of Medicine, University of Florida College of Medicine, Gainesville, FL, USA
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Oncology
  
• 出版者：Springer Netherlands
• ISSN：1573-7217

文摘

Reactive 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-κB 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-κB 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-κB 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-κB 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-κB signaling in MDA-MB-231 cells as RNAi-mediated knockdown of the NF-κB 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-κB transcriptional complex that, in turn, promotes aggressive breast cancer phenotype.