The effects of environmental aryl hydrocarbon receptor ligands on signaling and cell metabolism in cancer.

Dioxin and dioxin-like compounds are chlorinated organic pollutants formed during the manufacturing of other chemicals. Dioxins are ligands of the aryl hydrocarbon receptor (AHR), that induce AHR-mediated biochemical and toxic responses and are persistent in the environment. 2,3,7,8- tetrachlorodibenzo para dioxin (TCDD) is the prototypical AHR ligand and its effects represent dioxins. TCDD induces toxicity, immunosuppression and is a suspected tumor promoter. The role of TCDD in cancer however is debated and context-dependent. Environmental particulate matter, polycyclic aromatic hydrocarbons, perfluorooctane sulfonamide, endogenous AHR ligands, and cAMP signaling activate AHR through TCDD-independent pathways. The effect of activated AHR in cancer is context-dependent. The ability of FDA-approved drugs to modulate AHR activity has sparked interest in their repurposing for cancer therapy. TCDD by interfering with endogenous pathways, and overstimulating other endogenous pathways influences all stages of cancer. Herein we review signaling mechanisms that activate AHR and mechanisms by which activated AHR modulates signaling in cancer including affected metabolic pathways.

Biological Aspects of Cancer Health Disparities.

Racial and ethnic disparities span the continuum of cancer care and are driven by a complex interplay among social, psychosocial, lifestyle, environmental, health system, and biological determinants of health. Research is needed to identify these determinants of cancer health disparities and to develop interventions to achieve cancer health equity. Herein, we focus on the overall burden of ancestry-related molecular alterations, the functional significance of the alterations in hallmarks of cancer, and the implications of the alterations for precision oncology and immuno-oncology. In conclusion, we reflect on the importance of estimating ancestry, improving diverse racial and ethnic participation in cancer clinical trials, and examining the intersection among determinants of cancer health disparities.

The putative endogenous AHR ligand ITE reduces JAG1 and associated NOTCH1 signaling in triple negative breast cancer cells.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor. Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. TNBC expresses AHR and AHR ligands have anti-cancer activity in TNBC. The aggressiveness of TNBC is due in part to JAG1-NOTCH1 signaling. ITE is a putative endogenous AHR ligand. We show that ITE reduces the expression of JAG1 the amount of Notch 1 intracellular domain (NICD1) and the phosphorylation of STAT3 (at tyrosine 705) in TNBC MDA-MB-231 cells. The STAT3 inhibitor STATTIC also reduced JAG1. STAT3, thus, mediates regulation of JAG1 in MDA-MB-231 cells. Reducing the expression of JAG1 with short interfering RNA decreases the growth, migration and invasiveness of MDA-MB-231 cells. JAG1, therefore, has cellular effects in MDA-MB-231 cells under basal conditions. We consequently evaluated if exposing cells to greater amounts of JAG1 would counteract ITE cellular effects in MDA-MB-231 cells. The results show that JAG1 does not counteract the cellular effects of ITE. JAG1, thus, has no effect on growth or invasiveness in MDA-MB-231 cells treated with ITE. JAG1, therefore, has context dependent roles in MDA-MB-231 cells (basal versus ITE treatment). The results also show that other pathways, not inhibition of the JAG1-NOTCH1 pathway, are important for mediating the growth and invasive inhibitory effect of ITE on MDA-MB-231 cells.