Targeted inhibition of Wnt signaling with a bacterial toxin fragment suppresses breast cancer tumor-initiating/chemo-resistant cells

Abstract BRCA1 germ-line mutations are a major cause of hereditary breast cancer and BRCA1-deficient breast cancer shares many characteristics as sporadic basal-like breast cancer (BLBC). Effective therapeutic targets for BRCA1-deficient BLBC remain lacking. By utilizing a BRCA1-deficient BLBC mouse model based on intraductal injection of Krt8-Cre adenovirus to inactivate Brca1 and Trp53 in luminal mammary epithelial cells, here we report that the Wnt receptor Frizzled 7 (FZD7) serves as a biomarker and therapeutic target in the resulting mammary tumor cells and is particularly enriched in cancer stem cells / tumor-initiating cells (CSCs/TICs). Inhibiting FZD7-mediated Wnt signaling using a nontoxic FZD-binding fragment of C. difficile toxin B (TcdBFBD) attenuates growth of BRCA1-deficient tumor organoids and xenografted tumors, without damaging Wnt-sensitive tissues such as bones in vivo. Finally, FZD1/2/7-positive cells are enriched in chemotherapy-resistant cells in both BLBC and luminal breast tumors treated with cisplatin, and TcdBFBD synergizes strongly with cisplatin in inhibiting both tumor types. These findings demonstrate the therapeutic value for targeting FZD1/2/7 in treating breast cancers and establish TcdBFBD as a potential therapeutic agent targeting TICs and chemotherapy-resistant cancer cells.