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Activation of FOXO3a by the Green Tea Polyphenol Epigallocatechin-3-Gallate Induces Estrogen Receptor Expression Reversing Invasive Phenotype of Breast Cancer Cells

Department of Biochemistry and Women's Health Interdisciplinary Research Center, Boston University School of Medicine, Boston, Massachusetts

Requests for reprints: Gail E. Sonenshein, Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118; Phone: 617-638-4120; Fax: 617-638-4252; E-mail: gsonensh{at}bu.edu.

Previously, we showed that the bioactive green tea polyphenol epigallocatechin-3-gallate (EGCG) inhibits growth in soft agar of breast cancer cells with Her-2/neu overexpression. Using gene expression profiling, here we show that EGCG treatment of Her-2/neu–driven mammary tumor cells alters the expression of key regulators in the epithelial to mesenchymal transition (EMT) pathway, reducing invasive phenotype. Specifically, the epithelial genes E-cadherin, -catenin, MTA3, and estrogen receptor (ER) were up-regulated by EGCG, whereas the proinvasive snail gene was down-regulated. Consistently, EGCG inhibited branching colony growth and invasion in Matrigel. EGCG treatment similarly inhibited invasive phenotype of mouse mammary tumor cells driven by Nuclear Factor-B c-Rel and protein kinase CK2, frequently found overexpressed in human breast disease. Recently, we identified the Forkhead box O transcription factor FOXO3a as a major transcriptional regulator of ER. Given the pivotal role of ER in preventing EMT, we hypothesized that the activation of FOXO3a by EGCG plays an important role in the observed reversal of invasive phenotype in ER-positive breast cancer cells. EGCG treatment activated FOXO3a. Ectopic expression of a constitutively active FOXO3a overrode transforming growth factor-ß1–mediated invasive phenotype and induced a more epithelial phenotype, which was dependent on ER expression and signaling. Conversely, a dominant negative FOXO3a reduced epithelial phenotype of ER-low breast cancer cells. These results identify, for the first time, a role for FOXO3a in the inhibition of invasive phenotype in breast cancer cells with active ER signaling and elucidate a novel mechanism whereby EGCG represses EMT of breast cancer cells. [Cancer Res 2007;67(12):5763–70]

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				K. Belguise, S. Guo, S. Yang, A. E. Rogers, D. C. Seldin, D. H. Sherr, and G. E. Sonenshein Green Tea Polyphenols Reverse Cooperation between c-Rel and CK2 that Induces the Aryl Hydrocarbon Receptor, Slug, and an Invasive Phenotype Cancer Res., December 15, 2007; 67(24): 11742 - 11750. [Abstract] [Full Text] [PDF]