TY - JOUR
T1 - The WNT10B network is associated with survival and metastases in chemoresistant triple-negative breast cancer
AU - Ayachi, Ikbale El
AU - Fatima, Iram
AU - Wend, Peter
AU - Alva-Ornelas, Jackelyn A.
AU - Runke, Stephanie
AU - Kuenzinger, William L.
AU - Silva, Julio
AU - Silva, Wendy
AU - Gray, Joseph K.
AU - Lehr, Stephan
AU - Barch, Hilaire C.
AU - Krutilina, Raisa I.
AU - White, Andrew C.
AU - Cardiff, Robert
AU - Yee, Lisa D.
AU - Yang, Lily
AU - O'Regan, Ruth M.
AU - Lowry, William E.
AU - Seagroves, Tiffany N.
AU - Seewaldt, Victoria
AU - Krum, Susan A.
AU - Miranda-Carboni, Gustavo A.
PY - 2019/3/1
Y1 - 2019/3/1
N2 -
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.
AB -
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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85062260866&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-18-1069
DO - 10.1158/0008-5472.CAN-18-1069
M3 - Article
C2 - 30563890
AN - SCOPUS:85062260866
VL - 79
SP - 982
EP - 993
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 5
ER -