Aryl Hydrocarbon Receptor Activation by Imidacloprid as a Promoter of HER2(+) Breast Cancer Progression: In silico, in vitro and in vivo studies.

Breast cancer is the most common type of neoplasm in women globally. Growing evidence shows that people living in agricultural areas with heavy pesticide exposure have a higher risk of breast cancer. Imidacloprid (IMI) is a neonicotinoid insecticide used in large-scale agricultural systems, homes, and veterinary pharmaceutical products. The aryl hydrocarbon receptor (AhR) has been linked to breast cancer, and some pesticides can activate its signaling pathways. The G protein-coupled estrogen receptor (GPER) plays a fundamental role in epithelial-mesenchymal transition, relevant to the development of metastasis. In this work, we study IMI effects on human epidermal growth factor receptor 2-positive [HER2(+)] LM3 breast cancer cells, in a syngeneic model of breast tumors in mice, and in in silico analyses of the agonist/antagonist action of IMI on AhR. In LM3 cells, IMI promoted viability, proliferation and migration through AhR and GPER, and increased MMP-2 and MMP-9 activity. In the mouse model, IMI increased tumor growth and lung metastasis. In addition, IMI exposure significantly upregulated AhR protein expression and its canonical target gene cytochrome P450 1A1 mRNA in both models. Moreover, IMI enhanced GPER expression and the activation of ERK. The in silico results show that IMI occupies the AhR ligand-binding pocket with a considerably lower affinity than the full agonist TCDD. Our findings indicate that exposure to IMI promotes tumor growth and progression in a HER2(+) mouse model of breast cancer. Some of its effects can be explained by the insecticide's agonist activity on AhR.