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Published on: November 15, 2013
Green tea polyphenols reverse cooperation between c-Rel and CK2 that induces the aryl hydrocarbon receptor, slug, and
Karine Belguise1, Shangqin Guo, Shi Yang
1Departments of Biochemistry, Boston University School of Public Health, Boston, Massachusetts, USA.
Abstract:
Exposure to and bioaccumulation of lipophilic environmental pollutants, such as polycyclic aromatic hydrocarbons (PAHs), has been implicated in breast cancer. Treatment of female rats with the prototypic xenobiotic PAH 7,12-dimethylbenz(a)anthracene (DMBA) induces mammary tumors with an invasive phenotype. Here, we show that green tea prevents or reverses loss of the epithelial marker E-cadherin on the surface of DMBA-induced in situ cancers. To investigate the mechanism(s) leading to a less invasive phenotype, the effects of the green tea polyphenol epigallocatechin-3 gallate (EGCG) on mammary tumor cells were assessed. EGCG reversed epithelial to mesenchymal transition (EMT) in DMBA-treated NF-kappaB c-Rel-driven mammary tumor cells and reduced levels of c-Rel and the protein kinase CK2. Ectopic coexpression of c-Rel and CK2alpha in untransformed mammary epithelial cells was sufficient to induce a mesenchymal gene profile. Mammary tumors and cell lines derived from MMTV-c-Rel x CK2alpha bitransgenic mice displayed a highly invasive phenotype. Coexpression of c-Rel and CK2, or DMBA exposure induced the aryl hydrocarbon receptor (AhR) and putative target gene product Slug, an EMT master regulator, which could be reversed by EGCG treatment. Thus, activation of c-Rel and CK2 and downstream targets AhR and Slug by DMBA induces EMT; EGCG can inhibit this signaling.
Insights
Green tea, specifically epigallocatechin-3 gallate (EGCG), can prevent or reverse invasive breast cancer progression. EGCG inhibits key signaling pathways like NF-kappaB c-Rel and CK2, which are activated by polycyclic aromatic hydrocarbons (PAHs).
Area of Science:
- Environmental Health
- Oncology
- Molecular Biology
Background:
- Lipophilic environmental pollutants, including polycyclic aromatic hydrocarbons (PAHs), are linked to breast cancer development.
- Exposure to 7,12-dimethylbenz(a)anthracene (DMBA), a prototypic PAH, induces invasive mammary tumors in rats.
Purpose of the Study:
- To investigate the protective effects of green tea polyphenols against DMBA-induced mammary tumors.
- To elucidate the molecular mechanisms by which green tea compounds inhibit tumor invasion and epithelial-to-mesenchymal transition (EMT).
Main Methods:
- Treatment of female rats with DMBA to induce mammary tumors.
- Assessment of E-cadherin expression in DMBA-induced cancers.
- Evaluation of epigallocatechin-3 gallate (EGCG) effects on DMBA-treated mammary tumor cells.
- Analysis of NF-kappaB c-Rel, CK2, aryl hydrocarbon receptor (AhR), and Slug expression.
- Generation of MMTV-c-Rel x CK2alpha bitransgenic mice.
Main Results:
- Green tea (EGCG) prevented or reversed the loss of E-cadherin, an epithelial marker, in DMBA-induced in situ mammary cancers.
- EGCG reversed EMT in DMBA-treated NF-kappaB c-Rel-driven mammary tumor cells, reducing c-Rel and CK2 levels.
- Coexpression of c-Rel and CK2alpha induced a mesenchymal gene profile and a highly invasive phenotype in mammary cells and tumors.
- DMBA exposure or c-Rel/CK2 coexpression induced AhR and Slug, an EMT regulator, which EGCG reversed.
Conclusions:
- Activation of c-Rel and CK2 by DMBA induces EMT through downstream targets AhR and Slug.
- EGCG inhibits this signaling pathway, offering a potential therapeutic strategy against invasive breast cancer driven by environmental pollutants.
