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Aryl hydrocarbon receptor-mediated antiestrogenicity in MCF-7 cells: modulation of hormone-induced cell cycle enzymes
1Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas, 77843-4466, USA.
Abstract:
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibits 17beta-estradiol (E2) mammary tumor growth in rodents and in MCF-7 human breast cancer cells; however, the cell cycle genes/proteins which are inhibited have not been determined. Initial studies showed that treatment of MCF-7 cells with 10 nM E2 significantly increased cyclin D1 (protein and mRNA), cdk2- and cdk4-dependent kinase activities, and hyperphosphorylation of retinoblastoma (RB) protein. In contrast to results of recent studies (M. D. Planas-Silva and R. A. Weinberg, 1997, Mol. Cell. Biol. 17, 4059-4069), E2 induced dissociation of both cdk2 and cdk4 proteins from the p21 protein complex and significantly increased cdk7-dependent kinase activity. Treatment of MCF-7 cells with E2 also induced cdc25A phosphatase protein, which was accompanied by increased cdk2 and cdk4 proteins containing unphosphorylated tyrosine residues. Although TCDD alone has minimal effects on cell cycle proteins/enzymes, several E2-induced responses were significantly inhibited in MCF-7 cells cotreated with E2 plus TCDD. For example, TCDD significantly inhibited E2-induced hyperphosphorylation of RB, cyclin D1 protein, and cdk2-, cdk4-, and cdk7-dependent kinase activities. Inhibition of E2-induced cdk4-dependent kinase activity by TCDD may be related to the parallel decrease of E2-induced cyclin D1 protein, and inhibition of induced cdk2- and cdk4-dependent kinase activities may be due to significantly increased p21 levels in cells cotreated with TCDD plus E2. These results demonstrate that the antiestrogenic activity of TCDD is due to downregulation of several E2-induced cell cycle proteins/activities and this illustrates the complex cross talk between the aryl hydrocarbon and the E2 receptor signaling pathways.
Insights
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibits estrogen-induced (E2) breast cancer cell growth by downregulating key cell cycle proteins and activities. This study reveals complex cross-talk between TCDD and estrogen receptor signaling pathways.
Area of Science:
- Endocrinology
- Molecular Biology
- Cancer Research
Background:
- Estrogen (E2) promotes mammary tumor growth by regulating cell cycle proteins.
- The anti-estrogenic effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) on breast cancer are known, but the underlying cell cycle mechanisms are unclear.
Purpose of the Study:
- To determine the specific cell cycle genes and proteins affected by TCDD in the context of estrogen-induced MCF-7 breast cancer cell proliferation.
Main Methods:
- MCF-7 cells were treated with E2 alone or in combination with TCDD.
- Cell cycle proteins (cyclin D1, cdks, p21, cdc25A), kinase activities, and retinoblastoma (RB) protein phosphorylation were analyzed.
Main Results:
- E2 increased cyclin D1, cdk2/4/7 activity, and RB hyperphosphorylation.
- TCDD significantly inhibited E2-induced RB hyperphosphorylation, cyclin D1 levels, and cdk2/4/7 kinase activities.
- TCDD also increased p21 levels, potentially explaining the inhibition of cdk2/4 activities.
Conclusions:
- TCDD exhibits anti-estrogenic activity by downregulating E2-induced cell cycle proteins and kinase activities in breast cancer cells.
- This highlights intricate cross-talk between aryl hydrocarbon receptor and estrogen receptor signaling pathways.