Abstract

Aberrant activation of the Wnt/β-catenin pathway leads to the development of multiple cancers including breast cancer. There is an urgent need to develop therapeutic agents against this signaling pathway. In this study, we found that CDDO-Me could inhibit Wnt/β-catenin signaling mainly through targeting the LRP6 and FZD7 receptor complex. This compound induced the degradation and ubiquitination of LRP6 and Fzd7 via the lysosomal pathway. We further showed CDDO-Me mediated degradation of FZD7 in a LRP6 ectodomain-dependent manner. In breast cancer cells, treatment with CDDO-Me increased the degradation of LRP6 and Fzd7, reduced the levels of phosphorylated DVL2 and active β-catenin, resulting in downregulation of Wnt target genes and some cancer stem cell (CSC) marker genes. In a murine xenograft bearing MMTV-Wnt1-driven mammary tumor, administration of CDDO-Me significantly inhibited tumor growth, accompanied by reduced expression of phosphorylated and total LRP6, phosphorylated and unphosphorylated DVL2, active β-catenin, several Wnt target genes and CSC marker genes. Collectively, our results demonstrated that CDDO-Me is a potent Wnt/β-catenin signaling inhibitor and so may be a promising therapeutic agent against breast cancer.