The aryl hydrocarbon receptor antagonist, 3′methoxy-4′nitroflavone, attenuates 2,3,7,8-tetrachlorodibenzo-p-dioxin-dependent regulation of growth factor signaling and apoptosis in the MCF-10A cell line

Previous studies have demonstrated that 2,3,7,8 tetracholorodibenzo-p-dioxin (TCDD) mimics epidermal growth factor receptor (EGFR) signaling in the MCF-10A human mammary epithelial cell line and protects cells from EGF withdrawal-induced apoptosis. These effects appear to be due to the ability of TCDD to increase the expression of transforming growth factor-alpha (TGFalpha), a known EGFR ligand. Because TCDD's effects occurred at concentrations as low as 1 nM, a role for the aryl hydrocarbon receptor (AhR) was hypothesized. In the present study, 3'methoxy-4'nitroflavone (MNF), a known AhR antagonist, was used to analyze AhR signaling in this cell line. MNF suppressed TCDD-dependent dioxin response element (DRE)-driven luciferase activity at concentrations as low as 10 nM. In addition, MNF attenuated TCDD's ability to inhibit apoptosis and to activate Akt and Erk1,2, two EGFR-dependent signaling molecules. Finally, the TCDD-dependent increase in TGFalpha mRNA was also suppressed by MNF. MNF's effects on TCDD action in the MCF-10A cell line occurred at concentrations ranging from 1 nM for Akt phosphorylation and TGFa expression to 100 nM for inhibition of apoptosis. Attenuation of TCDD-dependent luciferase activity occurred at concentrations as low as 10 nM, which suggests that TCDD inhibits apoptosis in human mammary epithelial cells by multiple mechanisms. (C) 2003 Elsevier Science (USA). All rights reserved.