6,7,4 '-Trihydroxyisoflavone suppressed the estrogen receptor negative breast cancer growth via regulating glycogen synthase kinase-3 beta/beta-catenin signaling

Abstract

The hepatic metabolites of daidzein has been demonstrated to be more potent in chronic diseases than daidzein. However, the investigation of their roles in estrogen receptor (ER)-negative breast cancer is limited. Here, the hepatic metabolite of daidzein 6,7,4'-trihydroxyisoflavone inhibited cell proliferation, induced cell cycle arrest at G2/M phase, and regulated the expression of cyclin B, cyclin dependent kinase (CDK)-1 and CDK2 in MCF10DCIS.com ER-negative breast cancer cells. 6,7,4'-Trihydroxyisoflavone activated glycogen synthase kinase (GSK)-3 beta, and suppressed the nuclear translocation of beta-catenin. Inhibition of GSK3 beta by lithium chloride reversed the effect of 6,7,4'-trihydroxyisoflavone on beta-catenin localization, CDK1, CDK2 and cyclin B expression, and the proliferation of MCF10DCIS.com. In xenograft animal model, 6,7,4'-trihydroxyisoflavone inhibited tumor growth, and regulated GSK3 beta phosphorylation and beta-catenin nuclear localization. These results indicate that 6,7,4'-trihydroxyisoflavone suppressed ER-negative breast cancer growth through regulating GSK3 beta/beta-catenin signaling, and 6,7,4'-trihydroxyisoflavone may be a potent chemopreventive agent in regulating the ER negative human mammary carcinogenesis.