title: p38γ MAPK Is a Therapeutic Target for Triple-Negative Breast Cancer by Stimulation of Cancer Stem-Like Cell Expansion.
abstract: Triple-negative breast cancer (TNBC) is highly progressive and lacks established therapeutic targets. p38γ mitogen-activated protein kinase (MAPK) (gene name: MAPK12) is overexpressed in TNBC but how overexpressed p38γ contributes to TNBC remains unknown. Here, we show that p38γ activation promotes TNBC development and progression by stimulating cancer stem-like cell (CSC) expansion and may serve as a novel therapeutic target. p38γ silencing in TNBC cells reduces mammosphere formation and decreases expression levels of CSC drivers including Nanog, Oct3/4, and Sox2. Moreover, p38γ MAPK-forced expression alone is sufficient to stimulate CSC expansion and to induce epithelial cell transformation in vitro and in vivo. Furthermore, p38γ depends on its activity to stimulate CSC expansion and breast cancer progression, indicating a therapeutic opportunity by application of its pharmacological inhibitor. Indeed, the non-toxic p38γ specific pharmacological inhibitor pirfenidone selectively inhibits TNBC growth in vitro and/or in vivo and significantly decreases the CSC population. Mechanistically, p38γ stimulates Nanog transcription through c-Jun/AP-1 via a multi-protein complex formation. These results together demonstrate that p38γ can drive TNBC development and progression and may be a novel therapeutic target for TNBC by stimulating CSC expansion. Inhibiting p38γ activity with pirfenidone may be a novel strategy for the treatment of TNBC.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Ning
authors.initials: N
authors.lastname: Yin
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Shao
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Lepp
authors.affiliation: Laboratory Medicine, Guangzhou Medical University KingMed College, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.affiliation: Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Weiqing
authors.initials: W
authors.lastname: Jing
authors.affiliation: Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Bryon
authors.initials: B
authors.lastname: Johnson
authors.affiliation: Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Dwinell
authors.affiliation: Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Chitambar
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.|Research Services, Zablocki Veterans Affairs Medical Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Guan
authors.initials: G
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D048291:Mitogen-Activated Protein Kinase 12 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D011728:Pyridones / Q000008:administration & dosage*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*
chemical_list: D000970:Antineoplastic Agents; D011728:Pyridones; C093844:pirfenidone; D048291:Mitogen-Activated Protein Kinase 12
keywords: Cancer stem-like cells; Therapeutic target; Triple negative breast cancer; c-Jun/AP-1; p38γ MAPK