A fungicide, fenhexamid, is involved in the migration and angiogenesis in breast cancer cells expressing estrogen receptors

Abstract

Fenhexamid (Fen) is used to eradicate gray mold of fruits and vegetables leading to greater detection of its residual concentration in wine than other fungicides. Here, we further investigated the malign influence of Fen on the migration and angiogenesis via regulation of the estrogen receptor (ER) and phosphoinositide 3-kinase (PI3K) pathways in breast cancer models. ER-positive MCF-7 and ER-negative MDA-MB-231 breast cancer cells were exposed to 17β-estradiol (E2, 10−9 M), Fen (10−5 M and 10−7 M), ICI 182,780 (ICI; an ER antagonist, 10−8 M) or/and Pictilisib (Pic; a PI3K inhibitor, 10−7 M), and subsequently subjected to migration assay, live cell motility monitoring, trans-chamber assay, immunofluorescence, angiogenesis assay, tumor spheroid formation, and Western blot analysis. In MCF-7 cells, E2 and Fen induced cell migration by regulating the cell migration-related proteins. Although expressions of N-cadherin and Vimentin remained unchanged E2 and Fen induced the decrease of E-cadherin and Occludin in the immunofluorescence assay and Western blot analysis. In addition, Fen increased vessel formation in HUVEC cells. Furthermore, Fen treatment induced the formation of larger and denser tumor spheroids in MCF-7 cells. Western blot further confirmed the increased expressions of vascular endothelial growth factor (VEGF) and sex-determining region Y-box 2 (SOX2) after exposure to Fen. We conclude that Fen plays an important role as an endocrine-disrupting chemical in breast cancer migration and metastasis through the regulation of ER and PI3K signaling pathways.