Protein Cell. 2024 Mar 4. IF: 21.1 Microbiota enterotoxigenic Bacteroides fragilis-secreted BFT-1 promotes breast cancer cell stemness and chemoresistance through its functional receptor NOD1. Ma W, Zhang L, Chen W, Chang Z, Tu J, Qin Y, Yao Y, Dong M, Ding J, Li S, Li F, Deng Q, Yang Y, Feng T, Zhang F, Shao X, He X, Zhang L, Hu G, Liu Q, Jiang YZ, Zhu S, Xiao Z, Su D, Liu T, Liu S. Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Shanghai Medical College; Fudan University, Shanghai, China; The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China; Xijing Hospital, Fourth Military Medical University, Xi'an, China; University of Science and Technology of China, Hefei, China; The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China; Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China; Sun Yat-sen University Cancer Center, Guangzhou, China; Xiangya Hospital, Changsha, China; Tumor Hospital of Harbin Medical University, Harbin, China; Heilongjiang Academy of Medical Sciences, Harbin, China; Nanjing Medical University, Nanjing, China. Tumor-resident microbiota in breast cancer promote cancer initiation and malignant progression. However, targeting microbiota to improve the effects of breast cancer therapy has not been investigated in detail. Here, we evaluated the microbiota composition of breast tumors and found that enterotoxigenic Bacteroides fragilis (ETBF) was highly enriched in the tumors of patients who did not respond to taxane-based neoadjuvant chemotherapy. ETBF, albeit at low biomass, secreted the toxic protein BFT-1 to promote breast cancer cell stemness and chemoresistance. Mechanistic studies showed that BFT-1 directly bound to NOD1 and stabilized NOD1 protein. NOD1 was highly expressed on ALDH+ breast cancer stem cells (BCSCs) and cooperated with GAK to phosphorylate NUMB and promote its lysosomal degradation, thereby activating the NOTCH1-HEY1 signaling pathway to increase BCSCs. NOD1 inhibition and ETBF clearance increases the chemosensitivity of breast cancer by impairing BCSCs. KEYWORDS: BFT-1; ETBF; NOD1; breast cancer stem cell; chemoresistance; microbiota PMID: 38437016 DOI: 10.1093/procel/pwae005原文共享