| Autor: |
Gustavo A. Miranda-Carboni, Susan A. Krum, Victoria Seewaldt, Tiffany N. Seagroves, William E. Lowry, Ruth M. O'Regan, Lily Yang, Lisa D. Yee, Robert Cardiff, Andrew C. White, Raisa I. Krutilina, Hilaire C. Barch, Stephan Lehr, Joseph K. Gray, Wendy Silva, Julio Silva, William L. Kuenzinger, Stephanie Runke, Jackelyn A. Alva-Ornelas, Peter Wend, Iram Fatima, Ikbale El Ayachi |
| Rok vydání: |
2023 |
| DOI: |
10.1158/0008-5472.c.6511163.v1 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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