TY - JOUR T1 - CDDO-Me elicits anti-breast cancer activity by targeting LRP6 and FZD7 receptor complex JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.119.263434 SP - jpet.119.263434 AU - Liang Zhou AU - Zhongyuan Wang AU - Shubin Yu AU - Yanpeng Xiong AU - Jiaoyang Fan AU - Yansi Lyu AU - Zijie Su AU - Jiaxing Song AU - Shanshan Liu AU - Qi Sun AU - Desheng Lu Y1 - 2020/01/01 UR - http://jpet.aspetjournals.org/content/early/2020/02/03/jpet.119.263434.abstract N2 - 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.SIGNIFICANCE STATEMENT Current evidences showed that LRP6 and FZD7 membrane receptor complex play key effect on Wnt/β-catenin activation driven cancers. And block LRP6 or FZD7 by small molecular or antibody may help developing therapeutic approach for cancers including breast cancers. In this study we showed that the small molecular CDDO-ME can inhibits Wnt/β-catenin signaling pathway by inducing LRP6/FZD7 membrane receptor complex ubiquitination and degradation via a lysosomal pathway. And we also found that the ectodomain of LRP6 is very essential for CDDO-ME induced FZD7 degradation. Our results define a novel mechanism for anticancer action of CDDO-Me, and provide evidence for further clinical cancer research. ER -