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.

中文翻译：

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微生物群产肠毒素脆弱拟杆菌分泌的 BFT-1 通过其功能受体 NOD1 促进乳腺癌细胞干性和化疗耐药性。


乳腺癌中的肿瘤驻留微生物群促进癌症的发生和恶性进展。然而，针对微生物群来改善乳腺癌治疗效果的研究尚未得到详细研究。在这里，我们评估了乳腺肿瘤的微生物群组成，发现产肠毒素脆弱拟杆菌（ETBF）在对基于紫杉烷的新辅助化疗没有反应的患者的肿瘤中高度富集。 ETBF 尽管生物量较低，但会分泌有毒蛋白 BFT-1，以促进乳腺癌细胞干细胞性和化疗耐药性。机理研究表明，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协同磷酸化NUMB并促进其溶酶体降解，从而激活NOTCH1-HEY1信号通路以增加BCSCs。 NOD1 抑制和 ETBF 清除通过损害 BCSC 来增加乳腺癌的化疗敏感性。