Breast cancer, oxidative stress and NF-κB

A paper just published in the journal Breast Cancer Research and Treatment highlights how reactive oxygen species (ROS) activate pro-inflammatory NF-κB (nuclear factor kappa beta, also an oncogenic transcription factor) to promote more aggressive breast cancer, and that this can be ameliorated by N-acetyl-cysteine. The authors state:

"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."

DNA damage-responsive kinase ATM turns on NF-κB

They demonstrate that oxidative damage to DNA activates the kinase ATM which in turn revs up the tumor-promoting and inflammatory NF-κB:

"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."

In other words, by removing ATM from the chain prevents NF-κB from converting cells to the worse breast cancer phenotype.

N-acetyl cysteine (NAC) to the rescue

Clinicians involved in case management of autoimmune disorders are aware that N-acetyl cysteine (NAC) is one of the beneficent agents that help wind down NF-κB activity (a major player also in autoimmune inflammation). Here the authors show that NAC prevents NF-κB from turning on more harmful breast cancer genes:

"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."

Clinical note

Practitioners involved in breast cancer prevention and treatment should be attentive to patients' oxidative status which can be quantified with biomarkers such as the DNA oxidation product 8-Hydroxy-2-deoxyguanosine, and have practical familiarity with NAC and other agents that reduce ROS to acceptable levels and rein in NF-κB. The authors summarize:

"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."