title: c-Jun N-terminal kinase promotes stem cell phenotype in triple-negative breast cancer through upregulation of Notch1 via activation of c-Jun.
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.
authors.affiliation: Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: X
authors.initials: X
authors.lastname: Xie
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA.
authors.forename: T S
authors.initials: TS
authors.lastname: Kaoud
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Edupuganti
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kogawa
authors.affiliation: Division of Quantitative Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Y
authors.identifier: 0000-0002-6272-2776
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G B
authors.initials: GB
authors.lastname: Chauhan
authors.affiliation: Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: D N
authors.initials: DN
authors.lastname: Giannoukos
authors.affiliation: Division of Quantitative Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: D
authors.initials: D
authors.lastname: Tripathy
authors.affiliation: Division of Quantitative Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA.
authors.forename: K N
authors.initials: KN
authors.lastname: Dalby
authors.affiliation: Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Bartholomeusz
authors.affiliation: Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: N T
authors.initials: NT
authors.lastname: Ueno
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics*; D048670:MAP Kinase Kinase 4 / Q000235:genetics*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology; D010641:Phenotype; D051881:Receptor, Notch1 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4