Ah-Receptor as a central mediator of immunomodulation in the tumor microenvironment of breast cancer

Summary/Abstract Air pollution studies reported positive associations with the risk to develop breast cancer. Noteworthy, a stronger association of breast cancer risk was found with traffic related air pollution (TRAP) and higher polycyclic aromatic hydrocarbons (PAHs) exposure. PAHs result from combustion processes and derive from various sources (e.g. indoor fireplaces, wildfires, and vehicular traffic). Importantly, a stronger association of breast cancer has been identified with high air pollution exposure among African American and Japanese American women living in urban areas and near major roads presenting implications for health disparities and environmental justice. TRAP is a major ambient source of PAH exposure. PAHs such as benzo[a]pyrene (BaP) have been identified as ligands of the aryl hydrocarbon receptor (AhR). Activation of the AhR signaling pathway via environmental pollutants has been associated with the development of breast cancer. In a recent study, we showed that inhibition of AhR activity suppressed the onset and growth of mammary tumors in mice. Numerous reports suggest the important role that AhR plays in malignancies such as breast cancer and consequently the AhR has emerged as an attractive target for new drugs in cancer therapy. Moreover, recent studies and preliminary data reveal that the tumor microenvironment plays an important role in tumor promotion and progression of breast cancer. Tumor associated myeloid cells (TAMCs) such as myeloid- derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) with immune-suppressive activity play a key role in the tumor microenvironment of developing breast tumors. Preliminary data indicate that activation of AhR after TRAP exposure promote growth of mammary tumors and the accumulation of TAMCs. How TRAP exposure and activation of AhR signaling affects the function and accumulation of TAMCs to generate a pro-tumorigenic microenvironment and mediates growth and progression of mammary tumors is of critical importance. The study hypothesis is that elevated risks for breast cancer associated with exposure to TRAP is mediated via AhR signaling and tumor promotion through a pro-tumorigenic microenvironment enabling progressive tumor growth and metastases. While AhR has been studied in breast cancer cells in vitro, it is not yet known whether it mediates the tumor promoting effects of TRAP in a pre-clinical mouse model. This study would allow us to elucidate the mechanisms how the AhR controls the tumor promoting features of TAMCs in the tumor microenvironment stimulated by TRAP exposure. This project has the potential for high impact by identifying environmental risk factors and finding new innovative therapies to intervene and mitigate the development of breast cancer especially for people at higher risk through environmental exposure to air pollutants. The overall aim of this study was also the topic of the NIEHS/NCI workshop in 2022, “Complex exposures in breast cancer: unraveling the role of environmental mixtures”.