Mechanism of inhibition of MDA-MB-468 breast cancer cell growth by 2,3,7,8-tetrachlorodibenzo-p-dioxin

Treatment of estrogen receptor (ER)-negative MDA-MB-468 human breast cancercells with 10 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) inducedformation of a nuclear aryl hydrocarbon (Ah) receptor complex as determinedby ligand-binding and gel electrophoretic mobility shift assays. TCDD alsoinduced CYP1A1-dependent activity in MDA-MB-468 cells, which represents thefirst ER-negative Ah receptor-positive human breast cancer cell line thathas been identified. Treatment of this cell line with TCDD and relatedcompounds also caused a 50% inhibition of cell growth, which resembled thegrowth inhibitory effects previously reported for epidermal growth factor(EGF). However, EGF expression is minimal in this cell line and is notinduced by TCDD; moreover, EGF and TCDD induced a different pattern ofoncogene expression and apoptosis in MDA-MB-468 cells. In contrast, TCDDcaused a rapid and sustained induction of transforming growth factor alpha(TGF alpha) gene expression and secreted protein (nearly 2-fold); moreover,the growth-inhibitory effects of TCDD could be blocked by antibodies to theEGF receptor. In a separate experiment, it was shown that TGF alpha alsoinhibited growth of MDA-MB-468 cells. The results of this study indicatethat the mechanism of growth inhibition of MDA- MB-468 cells by TCDD is dueto induction of TGF alpha, which is a potent antimitogen in this cellbreast cancer line.