The WNT10B Network Is Associated with Survival and Metastases in Chemoresistant Triple-Negative Breast Cancer
| Autor: | Lisa D. Yee, Stephan Lehr, Jackelyn A. Alva-Ornelas, Ruth O'Regan, Peter Wend, C Hilaire, Tiffany N. Seagroves, Lily Yang, Robert D. Cardiff, Julio Silva, Ikbale El Ayachi, Raisa I. Krutilina, Gustavo A. Miranda-Carboni, Wendy Silva, Iram Fatima, Andrew C. White, William E. Lowry, Joseph Kerby Gray, Stephanie Runke, Victoria L. Seewaldt, William L. Kuenzinger, Susan A. Krum |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Drug Resistance Triple Negative Breast Neoplasms Transgenic Metastasis Mice 0302 clinical medicine Transcription Factor 4 Antineoplastic Combined Chemotherapy Protocols Neoplasm Metastasis Triple-negative breast cancer beta Catenin Cancer Tumor biology EZH2 Heterocyclic Wnt signaling pathway Acetylation Drug Synergism Middle Aged Survival Rate Oncology 5.1 Pharmaceuticals 030220 oncology & carcinogenesis Female Development of treatments and therapeutic interventions medicine.drug Lymphoid Enhancer-Binding Factor 1 Oncology and Carcinogenesis Mice Transgenic macromolecular substances Pyrimidinones Article Cell Line 03 medical and health sciences Bridged Bicyclo Compounds Breast cancer HMGA2 Cell Line Tumor Proto-Oncogene Proteins Breast Cancer Biomarkers Tumor medicine AXIN2 Animals Humans Doxorubicin Enhancer of Zeste Homolog 2 Protein Oncology & Carcinogenesis Alleles business.industry HMGA2 Protein Bridged Bicyclo Compounds Heterocyclic medicine.disease Wnt Proteins 030104 developmental biology Drug Resistance Neoplasm biology.protein Cancer research Neoplasm business Biomarkers |
| Zdroj: | Cancer research, vol 79, iss 5 |
| 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 |
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