Microbiota enterotoxigenic Bacteroides fragilis-secreted BFT-1 promotes breast cancer cell stemness and chemoresistance through its functional receptor NOD1
Received date: 03 Aug 2023
Accepted date: 05 Feb 2024
Copyright
Tumor-resident microbiota in breast cancer promotes 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 increase the chemosensitivity of breast cancer by impairing BCSCs.
Key words: microbiota; ETBF; BFT-1; NOD1; breast cancer stem cell; chemoresistance
Wei Ma , Lu Zhang , Weilong Chen , Zhaoxia Chang , Juchuanli Tu , Yuanyuan Qin , Yuwen Yao , Mengxue Dong , Jiajun Ding , Siqin Li , Fengkai Li , Qiaodan Deng , Yifei Yang , Tingting Feng , Fanrong Zhang , Xiying Shao , Xueyan He , Lixing Zhang , Guohong Hu , Quentin Liu , Yi-Zhou Jiang , Shu Zhu , Zhi Xiao , Dan Su , Tong Liu , Suling Liu . Microbiota enterotoxigenic Bacteroides fragilis-secreted BFT-1 promotes breast cancer cell stemness and chemoresistance through its functional receptor NOD1[J]. Protein & Cell, 2024 , 15(6) : 419 -440 . DOI: 10.1093/procel/pwae005
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