Details

Autor(en) / Beteiligte

• El Ayachi, Ikbale
• Fatima, Iram
• Wend, Peter
• Alva-Ornelas, Jackelyn A
• Runke, Stephanie
• Kuenzinger, William L
• Silva, Julio
• Silva, Wendy
• Gray, Joseph K
• Lehr, Stephan
• Barch, Hilaire C
• Krutilina, Raisa I
• White, Andrew C
• Cardiff, Robert
• Yee, Lisa D
• Yang, Lily
• O'Regan, Ruth M
• Lowry, William E
• Seagroves, Tiffany N
• Seewaldt, Victoria
• Krum, Susan A
• Miranda-Carboni, Gustavo A

Titel

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

Ist Teil von

• Cancer research (Chicago, Ill.), 2019-03, Vol.79 (5), p.982-993

Ort / Verlag

United States

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 - transgenic mice during metastasis, and 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 i . Combinatorial therapy of a WNT inhibitor with doxorubicin synergistically activated apoptosis , resensitized PDX-derived cells to doxorubicin, and repressed lung metastasis . 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. http://cancerres.aacrjournals.org/content/canres/79/5/982/F1.large.jpg.