Suppression of Wnt Signaling by the Green Tea Compound (–)-Epigallocatechin 3-Gallate (EGCG) in Invasive Breast Cancer Cells: REQUIREMENT OF THE TRANSCRIPTIONAL REPRESSOR HBP1

Abstract

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.