Prevention of apoptosis by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the MCF-10A cell line: Correlation with increased transforming growth factoralpha production

We have recently reported that 2,3,7,8-tetrachloradibenzo-p-dioxin (TCDD) i nhibits epidermal growth factor (EGF) withdrawal-induced apoptosis in the h uman mammary epithelial cell line MCF-10A. We hypothesized that TCDD-mediat ed inhibition of apoptosis,vas due to its ability to stimulate the EGF rece ptor (EGFR) pathway. Indeed, in the present studies, the EGFR inhibitor AG1 478 was able to prevent TCDD-, EGF-, and transforming growth factor alpha ( TGF-alpha)-dependent cell recovery and inhibition of apoptosis. These effec ts were specific for an EGFR-mediated pathway because cotreatment with AG82 5, an erbB2 inhibitor, had little effect on apoptosis. In addition, TCDD ma s able to mimic the EGF and TGF-alpha signaling as demonstrated by increasi ng Akt and extracellular signal regulated kinase 1,2 phosphorylation. These effects were dependent on EGFR activity because AG1478, but not AG825, was able to prevent EGF-, TGF-alpha, or TCDD-mediated Akt and extracellular si gnal-regulated kinase 1,2 phosphorylation. The ability of TCDD to stimulate the EGFR pathway and inhibit apoptosis may be due to the ability of TCDD t o increase expression of TGF-alpha, a ligand for EGFR. Treatment with 10 nM TCDD increased TGF-alpha mRNA at 2 h and TGF-alpha protein at 6 h. These d ata suggest a mechanism whereby TCDD is able to inhibit apoptosis in human mammary epithelial cells by stimulating TGF-alpha production, resulting in an autocrine effect.