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Triple-negative breast cancer (TNBC) commonly develops resistance to chemotherapy, yet markers predictive of chemoresistance in this disease are lacking. Here, we define WNT10B-dependent biomarkers for β-CATENIN/HMGA2/EZH2 signaling predictive of reduced relapse-free survival. Concordant expression of HMGA2 and EZH2 proteins is observed in MMTV-Wnt10bLacZ transgenic mice during metastasis, and Hmga2 haploinsufficiency decreased EZH2 protein expression, repressing lung metastasis. A novel autoregulatory loop interdependent on HMGA2 and EZH2 expression is essential for β-CATENIN/TCF-4/LEF-1 transcription. Mechanistically, both HMGA2 and EZH2 displaced Groucho/TLE1 from TCF-4 and served as gatekeepers for K49 acetylation on β-CATENIN, which is essential for transcription. In addition, we discovered that HMGA2-EZH2 interacts with the PRC2 complex. Absence of HMGA2 or EZH2 expression or chemical inhibition of Wnt signaling in a chemoresistant patient-derived xenograft (PDX) model of TNBC abolished visceral metastasis, repressing AXIN2, MYC, EZH2, and HMGA2 expression in vivo. Combinatorial therapy of a WNT inhibitor with doxorubicin synergistically activated apoptosis in vitro, resensitized PDX-derived cells to doxorubicin, and repressed lung metastasis in vivo. We propose that targeting the WNT10B biomarker network will provide improved outcomes for TNBC.Significance:These findings reveal targeting the WNT signaling pathway as a potential therapeutic strategy in triple-negative breast cancer.

Supplementary Section: 1) Seven supplementary figures and legends: A. Supplementary figure S1: TCGA analysis of WNT10B network. B. Supplementary figure S2: Human IHC analysis of WNT10B, HMGA2 and EZH2. C. Supplementary figure S3: Mouse IHC analysis of HMGA2 and EZH2. D. Supplementary figure S4: ChIP, qPCR and IB analysis on WNT10B/�CATENIN direct target genes. E. Supplementary figure S5: Characterization of CRISPR HMGA2KO and EZH2KO cells both in vitro and in vivo. F. Supplementary figure S6: Validation of WNT10B network on TNBC PDX tumors. G. Supplementary figure S7: Isobologram curves of ICG-001 and Doxorubicin activity. 2) Supplementary Material & Methods 3) Supplementary Table 1 (ST1) qPCR primers 4) Supplementary Table 2 (ST2) ChIP primers 5) 6) Supplementary Table 3 (ST3) drug combinatorial index