Faculty Collaboration Database

p38γ MAPK Is a Therapeutic Target for Triple-Negative Breast Cancer by Stimulation of Cancer Stem-Like Cell Expansion. Stem Cells 2015 Sep;33(9):2738-47

Date

06/17/2015

Pubmed ID

26077647

Pubmed Central ID

PMC4792188

DOI

10.1002/stem.2068

Scopus ID

2-s2.0-84940467357 (requires institutional sign-in at Scopus site)   30 Citations

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.

Author List

Qi X, Yin N, Ma S, Lepp A, Tang J, Jing W, Johnson B, Dwinell MB, Chitambar CR, Chen G

Authors

Guan Chen MD, PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Michael B. Dwinell PhD Director, Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Bryon D. Johnson PhD Adjunct Professor in the Medicine department at Medical College of Wisconsin
Xiao-Mei Qi MD Associate Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antineoplastic Agents
Cell Line, Tumor
Cell Proliferation
Female
HEK293 Cells
Humans
MCF-7 Cells
Mice, Inbred BALB C
Mice, Nude
Mitogen-Activated Protein Kinase 12
Neoplastic Stem Cells
Pyridones
Triple Negative Breast Neoplasms