EGFR and Hippo signaling pathways are involved in organophosphate esters-induced proliferation and migration of triple-negative breast cancer cells.

Abstract

The widespread application of organophosphate flame retardants has led to pervasive exposure to organophosphate esters (OPEs), prompting considerable concerns regarding their potential health risk to humans. Despite hints from previous research about OPEs' association with breast cancer, their specific effects and underlying mechanisms of triple-negative breast cancer (TNBC) remain unclear. In this study, we investigated the effects of four representative OPEs on cell proliferation, cell cycle regulation, migration, and the expression of genes and proteins associated with the epidermal growth factor receptor (EGFR) and Hippo signaling pathways in TNBC (MDA-MB-231) cells. Our findings revealed that treatment with 1-25μM triphenyl phosphate (TPHP) and tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) induced TNBC cell proliferation and accelerated cell cycle progression, with upregulation in MYC, CCND1, and BRCA1 mRNA. Moreover, exposure to 1-25μM TPHP, 10-25μM TDCIPP, and 1-10μM tris (2-chloroethyl) phosphate (TCEP) induced MMP2/9 mRNA expression and enhanced migratory capacity, except for 2-ethylhexyl diphenyl phosphate (EHDPP). Mechanistically, four OPEs treatments activated the EGFR-ERK1/2 and EGFR-PI3K/AKT signaling pathways by increasing the transcript of EGFR, ERK1/2, PI3K, and AKT mRNA. OPEs treatment also suppressed the Hippo signaling pathway by inhibiting the expression of MST1 mRNA and phosphorylation of LATS1, leading to the overactivation of YAP1 protein, thereby promoting TNBC cell proliferation and migration. In summary, our study elucidated that activation of the EGFR signaling pathway and suppression of the Hippo signaling pathway contributed to the proliferation, cell cycle dysregulation, and migration of TNBC cells following exposure to OPEs.