The WNT10B Network Is Associated with Survival and Metastases in Chemoresistant Triple-Negative Breast Cancer

摘要

Triple-negative breast cancer (TNBC) commonly develops resistance to chemotherapy, yetmarkers predictive of chemoresistance in this disease are lacking. Here, we define WNT10B-dependent biomarkers for beta-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 beta-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 beta-CATENIN, which is essential for transcription. In addition, we discovered thatHMGA2-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, resensitizedPDX-derived cells to doxorubicin, and repressed lungmetastasis in vivo. We propose that targeting the WNT10B biomarker network will provide improved outcomes for TNBC.