Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Cancer Institutes, Department of Oncology, Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Intelligent Pathology Institute and Department of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230071, China.
Protein Cell. 2024 May 28;15(6):419-440. doi: 10.1093/procel/pwae005.
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.
肿瘤驻留菌群促进乳腺癌的发生和恶性进展。然而，靶向菌群以改善乳腺癌治疗效果的研究尚未得到详细探讨。在这里，我们评估了乳腺癌肿瘤的菌群组成，发现对紫杉烷类新辅助化疗无反应的患者肿瘤中高度富集了产肠毒素脆弱拟杆菌（ETBF）。ETBF 尽管生物量较低，但分泌毒性蛋白 BFT-1 以促进乳腺癌细胞干性和化疗耐药性。机制研究表明，BFT-1 直接与 NOD1 结合并稳定 NOD1 蛋白。NOD1 在 ALDH+乳腺癌干细胞（BCSCs）上高表达，并与 GAK 合作使 NUMB 磷酸化并促进其溶酶体降解，从而激活 NOTCH1-HEY1 信号通路增加 BCSCs。NOD1 抑制和 ETBF 清除通过损害 BCSCs 增加乳腺癌的化疗敏感性。
