Activation, AhR leads to Increase, Inflammation

In triple negative breast cell lines (MDA-MB436, MDA-MB-231) and ER-positive cell lines, it has been shown that the activation of the AhR can lead to an increase in inflammation. (Bekki et al., 2015, Miller et al., 2005, Yamashita et al., 2018 May 1, Degner et al., 2009 Jan, Vogel et al., 2011 Aug 1, Kolasa et al., 2013 Apr 25, Vacher et al., 2018, Malik et al., 2019 Oct). The stressors mainly used to activate the AhR were TCDD followed by benzo[a]pyrene and 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhiP). After AhR inhibition (KO or antagonists), a decrease in inflammation biomarkers was found (Miller et al., 2005, Yamashita et al., 2018 May 1, Degner et al., 2009 Jan, Vogel et al., 2011 Aug 1, Kolasa et al., 2013 Apr 25). Assays evaluating cell inflammation were quantitative dosages of IL-6, IL-8 and Cox2 activity/expression. Cox-2 and IL-8 were amongst the top “gene concepts” retrieved by the PubTator Central tool, likewise, “inflammation” was frequently found as a disease concept. The most consensual pathway linking the AhR activation to cell inflammation was the NF-kB pathway (Vogel et al., 2011 Aug 1, Kolasa et al., 2013 Apr 25). Only half of the studies found a dose–response relationship (Miller et al., 2005, Kolasa et al., 2013 Apr 25, Malik et al., 2019 Oct). No studies were carried out in vivo for breast cancer and therefore the concordance and evidence were classified as “moderate”.

AOP 21 also found the association between AhR activation and inflammation via COX 2 (Aryl hydrocarbon receptor activation leading to early life stage mortality, via increased COX-2) with a weight of evidence classified as “high”. Indeed, the AhR/ARNT heterodimer links to the dioxin responsive elements which in turn up-regulates COX-2 (66,67].