The WNT10B network is associated with survival and metastases in chemoresistant triple-negative breast cancer

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

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

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 b-CATENIN/HMGA2/EZH2 signaling predictive of reduced relapse-free survival. Concordant expression of HMGA2 and EZH2 proteins is observed in MMTV-Wnt10b LacZ transgenic mice during metastasis, and Hmga2 haploin-sufficiency decreased EZH2 protein expression, repressing lung metastasis. A novel autoregulatory loop interdependent on HMGA2 and EZH2 expression is essential for b-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 b-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 synergisti-cally 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.

Original languageEnglish (US)
Pages (from-to)982-993
Number of pages12
JournalCancer Research
Volume79
Issue number5
DOIs
StatePublished - Mar 1 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Ayachi, I. E., Fatima, I., Wend, P., Alva-Ornelas, J. A., Runke, S., Kuenzinger, W. L., Silva, J., Silva, W., Gray, J. K., Lehr, S., Barch, H. C., Krutilina, R. I., White, A. C., Cardiff, R., Yee, L. D., Yang, L., O'Regan, R. M., Lowry, W. E., Seagroves, T. N., ... Miranda-Carboni, G. A. (2019). The WNT10B network is associated with survival and metastases in chemoresistant triple-negative breast cancer. Cancer Research, 79(5), 982-993. https://doi.org/10.1158/0008-5472.CAN-18-1069