Aryl hydrocarbon receptor-ligand hexachlorobenzene promotes immunosuppression leading to mammary tumor growth and metastasis in a HER2-positive syngeneic mouse model

Pesticide exposure has been established as a risk factor for breast cancer. Hexachlorobenzene (HCB) is an aryl hydrocarbon receptor (AhR) ligand. Mice bearing LM3 HER2(+) breast tumors were exposed to HCB (35 and 15 days). Tumor growth and lung metastases were evaluated, and key molecules were analyzed by western blot, immunofluorescence and RT-qPCR. Splenic and tumor infiltrating lymphocytes (TILs) were quantified by flow cytometry. Results showed that HCB (35 days) accelerates tumor growth and promotes lung metastases development. HCB upregulates AhR, CYP1A2, IDO1, COX-2 and VEGF expression. The pesticide reduces ERβ and increases GPER levels. Exposure to HCB decreases the content of CD8 + and regulatory T cells in the spleen and antigen-presenting cells in the tumor, without changes in TILs. HCB (15 days) suppresses CD4 + and CD8 + infiltration in tumors. Our findings indicate that HCB facilitates tumor progression in HER2(+) breast cancer, involving the dysregulation of ERs and pro-angiogenic factors. Likewise, AhR overexpression could be modulating the anti-tumor immune response, inducing immunosuppression.