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三阴性乳腺癌的雌激素受体、孕激素受体、人类表皮生长因子受体HER2均为阴性，对内分泌治疗和传统抗HER2靶向治疗基本无效，对紫杉类等化疗药物也非常容易耐药。近年来，科学家发现细菌除了广泛寄生于人体肠道，还可寄生于乳腺癌等多种癌症肿瘤细胞内，促进癌症的发生和恶化，并且影响免疫治疗效果，但是对化疗效果的影响尚不明确。 2024年3月4日，英国牛津大学出版社《蛋白质与细胞》在线发表复旦大学附属肿瘤医院马伟、张璐、陈为龙、柳素玲、哈尔滨医科大学附属肿瘤医院刘通、浙江省肿瘤医院苏丹、中南大学湘雅医院肖志等学者的研究报告，发现产肠毒素脆弱拟杆菌ETBF可促进三阴性乳腺癌对紫杉类化疗耐药，并且发现其关键治疗靶点。 该研究首先对乳腺肿瘤组织与周围正常组织的微生物群组成进行分析比较，发现ETBF高度聚集于紫杉类新辅助化疗无效患者的肿瘤内。虽然ETBF生物量较低，但是可分泌有毒蛋白质BFT-1，促进乳腺癌细胞干细胞化和化疗耐药。 该研究随后对三阴性乳腺癌细胞SUM159、MDA-MB-231和4T1进行机制分析，发现BFT-1可直接结合并稳定核苷酸结合寡聚化结构域蛋白NOD1。NOD1高表达于醛脱氢酶ALDH阳性乳腺癌干细胞，并与细胞周期蛋白G相关激酶GAK一起磷酸化内吞接头蛋白NUMB并促进其溶酶体降解，从而激活NOTCH1→HEY1信号通路，增加乳腺癌干细胞。 该研究最后利用诺地替尼-1抑制NOD1、利用甲硝唑清除ETBF，发现可显著减少乳腺癌干细胞，从而增强乳腺癌对紫杉类化疗药物多西他赛的敏感性。 因此，该研究明确了肿瘤干细胞高表达NOD1引起乳腺癌细胞与ETBF相互作用并导致乳腺癌对多西他赛耐药的作用机制和具体分子机制，发现预测乳腺癌对多西他赛耐药的分子标志物，并提出逆转乳腺癌对多西他赛耐药的三药联合治疗新策略，为解析肠道菌群调控乳腺癌化疗效果提供理论依据，为进一步理解乳腺癌肿瘤微生态、探索乳腺癌治疗新策略带来了希望。Protein Cell. 2024 Mar 4. IF: 21.1Microbiota 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; microbiotaDOI: 10.1093/procel/pwae005
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