Abstract
c-Jun N-terminal kinase (JNK) plays a vital role in malignant transformation of different cancers, and JNK is highly activated in basal-like triple-negative breast cancer (TNBC). However, the roles of JNK in regulating cancer stem-like cell (CSC) phenotype and tumorigenesis in TNBC are not well defined. JNK is known to mediate many cellular events via activating c-Jun. Here, we found that JNK regulated c-Jun activation in TNBC cells and that JNK activation correlated with c-Jun activation in TNBC tumors. Furthermore, the expression level of c-Jun was significantly higher in TNBC tumors than in non-TNBC tumors, and high c-Jun mRNA level was associated with shorter disease-free survival of patients with TNBC. Thus, we hypothesized that the JNK/c-Jun signaling pathway contributes to TNBC tumorigenesis. We found that knockdown of JNK1 or JNK2 or treatment with JNK-IN-8, an adenosine triphosphate-competitive irreversible pan-JNK inhibitor, significantly reduced cell proliferation, the ALDH1+ and CD44+/CD24− CSC subpopulations, and mammosphere formation, indicating that JNK promotes CSC self-renewal and maintenance in TNBC. We further demonstrated that both JNK1 and JNK2 regulated Notch1 transcription via activation of c-Jun and that the JNK/c-Jun signaling pathway promoted CSC phenotype through Notch1 signaling in TNBC. In a TNBC xenograft mouse model, JNK-IN-8 significantly suppressed tumor growth in a dose-dependent manner by inhibiting acquisition of the CSC phenotype. Taken together, our data demonstrate that JNK regulates TNBC tumorigenesis by promoting CSC phenotype through Notch1 signaling via activation of c-Jun and indicate that JNK/c-Jun/Notch1 signaling is a potential therapeutic target for TNBC.
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Acknowledgements
The MIGR1 vectors were generous gifts from Dr Khaled A. Hassan (University of Michigan, Ann Arbor, MI). We thank Naoko Matsuda of the Department of Breast Medical Oncology at MD Anderson for assistance with the RPPA data analysis. We acknowledge Stephanie P Deming of the Department of Scientific Publications at MD Anderson for editorial assistance and Wendy Schober, Nalini Patel and Duncan Mak of the Flow Cytometry and Cellular Imaging Facility at MD Anderson for assistance with cell cycle distribution and stem cell subpopulation analyses. This work was supported by MD Anderson Cancer Center Inflammatory Breast Cancer funds (105655) and Nylene Eckles funds (101478) to Naoto T Ueno; startup funds from MD Anderson Cancer Center (111411) to Chandra Bartholomeusz; Cancer Prevention and Research Institute of Texas (RP140648 and RP140649) to Kevin N Dalby; a Susan G Komen for the Cure Postdoctoral Fellowship to Xuemei Xie (KG111170); and National Institutes of Health Cancer Center Support Grant to MD Anderson Cancer Center (CA016672).
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Xie, X., Kaoud, T., Edupuganti, R. et al. c-Jun N-terminal kinase promotes stem cell phenotype in triple-negative breast cancer through upregulation of Notch1 via activation of c-Jun. Oncogene 36, 2599–2608 (2017). https://doi.org/10.1038/onc.2016.417
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DOI: https://doi.org/10.1038/onc.2016.417
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