He, AinaTian, SonghaiKopper, OdedHoran, Daniel J.Chen, PengBronson, Roderick T.Sheng, RenWu, HaoSui, LufeiZhou, KunTao, LiangWu, QuanHuang, YujingShen, ZanHan, SenChen, XueqingChen, HongHe, XiRobling, Alexander G.Jin, RongshengClevers, HansXiang, DongxiLi, ZheDong, Min2024-04-162024-04-162023-11-09He A, Tian S, Kopper O, et al. Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth. He A, Tian S, Kopper O, et al. Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth. PLoS Biol. 2023;21(11):e3002353. Published 2023 Nov 9. doi:10.1371/journal.pbio.3002353. 2023;21(11):e3002353. Published 2023 Nov 9. doi:10.1371/journal.pbio.3002353https://hdl.handle.net/1805/40048Wnt signaling pathways are transmitted via 10 homologous frizzled receptors (FZD1-10) in humans. Reagents broadly inhibiting Wnt signaling pathways reduce growth and metastasis of many tumors, but their therapeutic development has been hampered by the side effect. Inhibitors targeting specific Wnt-FZD pair(s) enriched in cancer cells may reduce side effect, but the therapeutic effect of narrow-spectrum Wnt-FZD inhibitors remains to be established in vivo. Here, we developed a fragment of C. difficile toxin B (TcdBFBD), which recognizes and inhibits a subclass of FZDs, FZD1/2/7, and examined whether targeting this FZD subgroup may offer therapeutic benefits for treating breast cancer models in mice. Utilizing 2 basal-like and 1 luminal-like breast cancer models, we found that TcdBFBD reduces tumor-initiating cells and attenuates growth of basal-like mammary tumor organoids and xenografted tumors, without damaging Wnt-sensitive tissues such as bones in vivo. Furthermore, FZD1/2/7-positive cells are enriched in chemotherapy-resistant cells in both basal-like and luminal mammary tumors treated with cisplatin, and TcdBFBD synergizes strongly with cisplatin in inhibiting both tumor types. These data demonstrate the therapeutic value of narrow-spectrum Wnt signaling inhibitor in treating breast cancers.en-USAttribution 4.0 InternationalBacterial toxinsBreast neoplasmsClostridioides difficileCisplatinWnt signaling pathwayTargeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growthArticle