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J. Biol. Chem., Vol. 281, Issue 16, 10865-10875, April 21, 2006

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Suppression of Wnt Signaling by the Green Tea Compound (–)-Epigallocatechin 3-Gallate (EGCG) in Invasive Breast Cancer Cells

REQUIREMENT OF THE TRANSCRIPTIONAL REPRESSOR HBP1^*

Jiyoung Kim^¶, Xiaowei Zhang, Kimberly M. Rieger-Christ^||, Ian C. Summerhayes^||, David E. Wazer^¶, K. Eric Paulson^¶, and Amy S. Yee¹

From the Department of Biochemistry, Tufts University School of Medicine, the Program of Cell and Molecular Nutrition, School of Nutrition Science and Policy, Tufts University, the ^¶Department of Radiation Oncology, Tufts-New England Medical Center, Boston, Massachusetts 02111, and the ^||Cell and Molecular Biology Laboratory, R. E. Wise M.D. Research and Education Institute, The Lahey Clinic, Burlington, Massachusetts 01805

Genetic and biochemical de-regulation of Wnt signaling is correlated with breast and other cancers. Our goal was to identify compounds that block Wnt signaling as a first step toward investigating new strategies for suppression of invasive and other breast cancers. In a limited phytonutrient screen, EGCG ((–)-epigallocatechin 3-gallate), the major phytochemical in green tea, emerged as an intriguing candidate. Epidemiological studies have associated green tea consumption with reduced recurrence of invasive and other breast cancers. Wnt signaling was inhibited by EGCG in a dose-dependent manner in breast cancer cells. The apparent mechanism targeted the HBP1 transcriptional repressor, which we had previously characterized as a suppressor of Wnt signaling. EGCG treatment induced HBP1 transcriptional repressor levels through an increase in HBP1 mRNA stability, but not transcriptional initiation. To test functionality, DNA-based short hairpin RNA (shRNA) was used to knockdown the endogenous HBP1 gene. Consistently, the HBP1 knockdown lines had reduced sensitivity to EGCG in the suppression of Wnt signaling and of a target gene (c-MYC). Because our ongoing studies clinically link abrogation of HBP1 with invasive breast cancer, we tested if EGCG also regulated biological functions associated with de-regulated Wnt signaling and with invasive breast cancer. EGCG reduced both breast cancer cell tumorigenic proliferation and invasiveness in an HBP1-dependent manner. Together, the emerging mechanism is that EGCG blocks Wnt signaling by inducing the HBP1 transcriptional repressor and inhibits aspects of invasive breast cancer. These studies provide a framework for considering future studies in breast cancer treatment and prevention.

Received for publication, December 15, 2005 , and in revised form, February 16, 2006.

^* This work was supported by National Institutes of Health Grants CA-94187 and CA-104236 (to A. S. Y.), grants from the David E. Wazer breast cancer fund at the New England Medical Center and the Susan B. Komen Foundation (to K. E. P), National Institutes of Health Grant 1DK59400 (to I. C. S.), and at Tufts New England Medical Center Digestive Disease Center P30-DK34928 for the molecular biology and tissue culture cores. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 136 Harrison Ave., Boston, MA 02111. Tel.: 617-636-6850; Fax: 617-636-2409; E-mail: amy.yee{at}tufts.edu.

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