p38γ MAPK Is a Therapeutic Target for Triple-Negative Breast Cancer by Stimulation of Cancer Stem-Like Cell Expansion

Triple-negative breast cancer (TNBC) is highly progressive and lacks established therapeutic targets. p38 gamma mitogen-activated protein kinase (MAPK) (gene name: MAPK12) is overexpressed in TNBC but how overexpressed p38 gamma contributes to TNBC remains unknown. Here, we show that p38 gamma activation promotes TNBC development and progression by stimulating cancer stem-like cell (CSC) expansion and may serve as a novel therapeutic target. p38 gamma silencing in TNBC cells reduces mammosphere formation and decreases expression levels of CSC drivers including Nanog, Oct3/4, and Sox2. Moreover, p38 gamma MAPK-forced expression alone is sufficient to stimulate CSC expansion and to induce epithelial cell transformation in vitro and in vivo. Furthermore, p38 gamma 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 p38 gamma specific pharmacological inhibitor pirfenidone selectively inhibits TNBC growth in vitro and/or in vivo and significantly decreases the CSC population. Mechanistically, p38 gamma stimulates Nanog transcription through c-Jun/AP-1 via a multi-protein complex formation. These results together demonstrate that p38 gamma can drive TNBC development and progression and may be a novel therapeutic target for TNBC by stimulating CSC expansion. Inhibiting p38 gamma activity with pirfenidone may be a novel strategy for the treatment of TNBC.