Effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) on Insulin-Induced Responses in MCF-7 Human Breast Cancer Cells

Abstract

Insulin stimulated proliferation of MCF-7 human breast cancer cells in serum-free medium, whereas 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,7,8-tetrachlorodibenzofuran (TCDF) did not affect cell growth. In cells cotreated with insulin plus TCDD or TCDF, insulin-induced cell proliferation and [3H]thymidine incorporation were inhibited. In contrast, α-naphthoflavone, a partial aryl hydrocarbon (Ah) receptor antagonist, blocked the inhibitory effects of TCDD, suggesting that the Ah receptor was involved in TCDD-induced responses in MCF-7 cells. TCDD alone did not affectKdandBmaxvalues for binding of [125I]insulin to the insulin receptor (IR); however, in MCF-7 cells cotreated with insulin plus TCDD, the insulin-inducedKdvalue for IR–ligand binding was decreased and theBmaxvalue was increased. TCDD induced IR mRNA levels and inhibited several other insulin-induced responses includingc-fosprotooncogene expression, phosphorylation of the insulin receptor, and a 185-kDa protein in MCF-7 cells.