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J Steroid Biochem Mol Biol. 1993 Mar;44(3):251-61.

Interaction of 2,3,7,8-tetrachlorodibenzo-p-dioxin, 12-O-tetradecanoylphorbol-13-acetate (TPA) and 17 beta-estradiol in MCF-7 human breast cancer cells.

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  • 1Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843-4466.


2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and 12-O-tetradecanoylphorbol-13-acetate (TPA) are both tumor promoters which act through different mechanisms. In MCF-7 human breast cancer cells, both TCDD and TPA inhibited constitutive and 17 beta-estradiol-induced cell proliferation but showed no apparent interactive effects. TCDD also inhibited the 17 beta-estradiol-induced secretion of the 52-kDa protein (procathepsin D) and induced CYP1A1 gene expression whereas TPA alone was inactive for these responses. Moreover, TPA did not modulate the TCDD-mediated antiestrogenic or induction responses and did not decrease levels of the nuclear Ah receptor complex as determined in a gel mobility shift assay using a 32P-dioxin responsive element (DRE). The interactions of TPA and TCDD on the metabolism of [13C]glucose to [13C]lactate was also investigated using 13C-nuclear magnetic resonance spectroscopy. The rate of formation of [13C]lactate from [13C]glucose in MCF-7 cells treated with DMSO (control), 1 nM 17 beta-estradiol, 1 nM TCDD, 1 nM TCDD plus 1 nM 17 beta-estradiol, and 0.1 ng/ml TPA plus 1 nM 17 beta-estradiol was 28, 48, 20, 22 and 50 fmol lactate formed/cell/h, respectively. Thus, TCDD, but not TPA, inhibited this estrogen-induced response. However, a comparison of the rate of lactate formation in cells treated with TCDD plus 17 beta-estradiol (22 fmol/cell/h) or TCDD plus 17 beta-estradiol plus TPA (61 fmol/cell/h) showed that TPA significantly inhibited the TCDD-mediated antiestrogenic response. The results of these studies in MCF-7 cells demonstrate that the interactions of TCDD and TPA are highly response-specific and do not involve TPA-mediated downregulation of the nuclear Ah receptor complex.

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