Microbiota enterotoxigenic Bacteroides fragilis-secreted BFT-1 promotes breast cancer cell stemness and chemoresistance through its functional receptor NOD1

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.

PMN-MDSCs modulated by CCL20 from cancer cells promoted breast cancer cell stemness through CXCL2-CXCR2 pathway

Our previous studies have showed that C-C motif chemokine ligand 20(CCL20)advanced tumor progression and enhanced the chemoresistance of cancer cells by positively regulating breast cancer stem cell(BCSC)self-renewal.However,it is unclear whether CCL20 affects breast cancer progression by remodeling the tumor microenvironment(TME).Here,we observed that polymorphonuclear myeloid-derived suppressor cells(PMN-MDSCs)were remarkably enriched in TME of CCL20-overexpressing cancer cell orthotopic allograft tumors.Mechanistically,CCL20 activated the differentiation of granulocyte-monocyte progenitors(GMPs)via its receptor C-C motif chemokine receptor 6(CCR6)leading to the PMN-MDSC expansion.PMN-MDSCs from CCL20-overexpressing cell orthotopic allograft tumors(CCL20-modulated PMN-MDSCs)secreted amounts of C-X-C motif chemokine ligand 2(CXCL2)and increased ALDH+BCSCs via activating CXCR2/NOTCH1/HEY1 signaling pathway.Furthermore,C-X-C motif chemokine receptor 2(CXCR2)antagonist SB225002 enhanced the docetaxel(DTX)effects on tumor growth by decreasing BCSCs in CCL20high-expressing tumors.These findings elucidated how CCL20 modulated the TME to promote cancer development,indicating a new therapeutic strategy by interfering with the interaction between PMN-MDSCs and BCSCs in breast cancer,especially in CCL20high-expressing breast cancer.

Discovery of a first-in-class ANXA3 degrader for the treatment of triple-negative breast cancer

Triple-negative breast cancer(TNBC)is a nasty disease with extremely high malignancy and poor prognosis.Annexin A3(ANXA3)is a potential prognosis biomarker,displaying an excellent correlation of ANXA3 overexpression with patients'poor prognosis.Silencing the expression of ANXA3effectively inhibits the proliferation and metastasis of TNBC,suggesting that ANXA3 can be a promising therapeutic target to treat TNBC.Herein,we report a first-in-class ANXA3-targeted small molecule(R)-SL18,which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells.(R)-SL18 directly bound to ANXA3 and increased its ubiquitination,thereby inducing ANXA3 degradation with moderate family selectivity.Importantly,(R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model.Furthermore,(R)-SL18 could reduce theβ-catenin level,and accordingly inhibit the Wnt/β-catenin signaling pathway in TNBC cells.Collectively,our data suggested that targeting degradation of ANXA3 by(R)-SL18 possesses the potential to treat TNBC.