Green tea polyphenols reverse cooperation between c-Rel and CK2 that induces the aryl hydrocarbon receptor, slug, and an invasive phenotype.
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.
Belguise
Karine
K
Departments of Biochemistry, Boston University School of Public Health, Boston, Massachusetts, USA.
Guo
Shangqin
S
Yang
Shi
S
Rogers
Adrianne E
AE
Seldin
David C
DC
Sherr
David H
DH
Sonenshein
Gail E
GE
D015127:9,10-Dimethyl-1,2-benzanthracene; D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D000818:Animals; D001628:Beverages; D002278:Carcinoma in Situ / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D047390:Casein Kinase II / Q000502:physiology*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000235:genetics; D010636:Phenols / Q000494:pharmacology*; D010641:Phenotype; D059808:Polyphenols; D020569:Proto-Oncogene Proteins c-rel / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics*
D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; D020569:Proto-Oncogene Proteins c-rel; C000604449:Snai2 protein, mouse; C000604450:Snai2 protein, rat; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D015127:9,10-Dimethyl-1,2-benzanthracene; D047390:Casein Kinase II