Environmental exposure and the role of AhR in the tumor microenvironment of breast cancer

Abstract

Activation of the aryl hydrocarbon receptor (AhR) through environmental exposure to chemicals including polycyclic aromatic hydrocarbons (PAHs) and polychlorinated dibenzo-p-dioxins (PCDDs) can lead to severe adverse health effects and increase the risk of breast cancer. This review considers several mechanisms which link the tumor promoting effects of environmental pollutants with the AhR signaling pathway, contributing to the development and progression of breast cancer. We explore AhR’s function in shaping the tumor microenvironment, modifying immune tolerance, and regulating cancer stemness, driving breast cancer chemoresistance and metastasis. The complexity of AhR, with evidence for both oncogenic and tumor suppressor roles is discussed. We propose that AhR functions as a “molecular bridge”, linking disproportionate toxin exposure and policies which underlie environmental injustice with tumor cell behaviors which drive poor patient outcomes.

Lung cancer associated with combustion particles and fine particulate matter (PM2.5) - The roles of polycyclic aromatic hydrocarbons (PAHs) and the aryl hydrocarbon receptor (AhR)

“…AhR plays a central role in cancer promotion pointing towards the non-genotoxic properties of PAHs. For instance, the AhR may directly regulate inflammatory responses and immune cells in the tumor microenvironment [ 113 ]. Moreover, nuclear AhR translocation, a hallmark of AhR activation, appears to be more common in female non-smokers with ADC, and it is associated with EGFR mutations [ 114 – 116 ].…”

“…Consequently, the AhR may play a critical role in the TME of various cancer types by modulating the recruitment and function of infiltrating immune cells. Because AhR can be regulated by small molecules, the AhR has been suggested to be an attractive target for the tumor microenvironment and immunotherapy to treat cancer [ 113 , 364 , 365 ].…”

The kynurenine pathway presents multi-faceted metabolic vulnerabilities in cancer

“…It is also important to consider additional factors that may influence KP activity such as diet ( 67 ) and environmental contributors ( 181 , 182 ). Liang and colleagues demonstrated that nicotine-derived nitrosaminoketone (NNK) upregulates IDO1 via α7 nicotinic acetylcholine receptor (α7nAChR)-mediated activation of the factor c-Jun in lung tumors.…”

“…Moreover, individuals with non-small cell lung cancer who smoked had higher tumoral IDO1 levels and lower Trp/Kyn ratios compared patients who never smoked, further suggesting that smoking impacts KP activity ( 181 ). Exposure to other environmental toxicants can also activate AhR signaling ( 182 ), which may upregulate IDO expression resulting in immune suppression ( 48 ).…”

Comment on “Application of the Key Characteristics Framework to Identify Potential Breast Carcinogens Using Publicly Available in Vivo , in Vitro , and in Silico Data”

“… 6 – 8 Interestingly, the causal link between the action of these pollutants and certain cellular characteristics specific to metastases can also be established, involving the aryl hydrocarbon receptor, for example. 9 , 10 …”