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 Seagroves, Victoria Seewaldt & 2 others Susan Miranda, Gustavo Miranda-Carboni

Research output: Contribution to journalArticle

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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

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Triple Negative Breast Neoplasms
Neoplasm Metastasis
Survival
Heterografts
Doxorubicin
HMGA2 Protein
Biomarkers
Lung
Acetylation
Transgenic Mice
Apoptosis
Recurrence
Drug Therapy
Therapeutics
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

The WNT10B network is associated with survival and metastases in chemoresistant triple-negative breast cancer. / Ayachi, Ikbale El; 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; Seewaldt, Victoria; Miranda, Susan; Miranda-Carboni, Gustavo.

In: Cancer Research, Vol. 79, No. 5, 01.03.2019, p. 982-993.

Research output: Contribution to journalArticle

Ayachi, IE, Fatima, I, Wend, P, Alva-Ornelas, JA, Runke, S, Kuenzinger, WL, Silva, J, Silva, W, Gray, JK, Lehr, S, Barch, HC, Krutilina, RI, White, AC, Cardiff, R, Yee, LD, Yang, L, O'Regan, RM, Lowry, WE, Seagroves, T, Seewaldt, V, Miranda, S & Miranda-Carboni, G 2019, 'The WNT10B network is associated with survival and metastases in chemoresistant triple-negative breast cancer', Cancer Research, vol. 79, no. 5, pp. 982-993. https://doi.org/10.1158/0008-5472.CAN-18-1069
Ayachi, Ikbale El ; 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 ; Seewaldt, Victoria ; Miranda, Susan ; Miranda-Carboni, Gustavo. / The WNT10B network is associated with survival and metastases in chemoresistant triple-negative breast cancer. In: Cancer Research. 2019 ; Vol. 79, No. 5. pp. 982-993.
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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.",
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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

AU - Seewaldt, Victoria

AU - Miranda, Susan

AU - Miranda-Carboni, Gustavo

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.

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