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 SP - 149 LP - 159 DO - 10.1124/jpet.119.263434 VL - 373 IS - 1 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 - 2020/04/01 UR - http://jpet.aspetjournals.org/content/373/1/149.abstract N2 - Aberrant activation of the Wnt/β-catenin pathway leads to the development of multiple cancers, including breast cancer. Development of therapeutic agents against this signaling pathway is an urgent need. In this study, we found that 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid–methyl ester (CDDO-Me) could inhibit Wnt/β-catenin signaling mainly through targeting the low-density lipoprotein receptor–related protein (LRP) 6 and Frizzled (FZD) 7 receptor complex. This compound induced the degradation and ubiquitination of LRP6 and Fzd7 via the lysosomal pathway. We further showed that CDDO-Me mediated the degradation of FZD7 in an LRP6 ectodomain-dependent manner. In breast cancer cells, treatment with CDDO-Me increased the degradation of LRP6 and FZD7 and reduced the levels of phosphorylated Disheveled (DVL) 2 and active β-catenin, resulting in the downregulation of Wnt target genes and several cancer stem cell (CSC) marker genes. In a murine xenograft bearing mouse mammary tumor virus (MMTV)-Wnt1–driven mammary tumor, administration of CDDO-Me significantly inhibited tumor growth and was 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, the results of our study present that CDDO-Me is a potent Wnt/β-catenin signaling inhibitor that may be a promising therapeutic agent against breast cancer.SIGNIFICANCE STATEMENT Blocking the membrane receptor complex consisting of low-density lipoprotein receptor–related protein (LRP) 6 and Frizzled (FZD) 7 may help developing therapeutic approaches for cancers, including breast cancers. Our study indicates that 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid–methyl ester (CDDO-Me) can inhibit Wnt/β-catenin signaling by inducing the ubiquitination and degradation of LRP6/FZD7 membrane receptor complex via a lysosomal pathway. We also found that the ectodomain of LRP6 is essential for CDDO-Me–induced FZD7 degradation. Defining CDDO-Me as a novel inhibitor of Wnt/β-catenin signaling, our results provide insight into the mechanism of its anticancer activity. ER -