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.

Role of p38γ MAPK in regulation of EMT and cancer stem cells

“…p38γ MAPK is activated through both overexpression and phosphorylation [3]. Asp to Ala mutation in the phosphorylation lip (D179) made p38γ MAPK constitutively active [14].…”

Targeting FOSB with a cationic antimicrobial peptide, TP4, for treatment of triple-negative breast cancer

“…JNKs and p38 both possess oncogenic or tumor-suppressive functions [48]. In TNBC, both kinases are required for tumor development and progression, as mediated through cJUN/AP-1-activated signaling pathways [38, 49, 50]. Here, the decrease of JNKs and p38 activities in MB231 cells may destabilize cJUN/FRA1 or other cJUN/AP-1 complexes, leading to the transcriptional inactivation of genes involved in TNBC cell progression.…”

Frequency of MicroRNA Response Elements Identifies Pathologically Relevant Signaling Pathways in Cancers

“…Previous studies have shown this pathway to be highly prevalent in TN breast cancer as opposed to other breast cancer subtypes (Hoeflich et al 2009; Balko et al 2012; Hashimoto et al 2014), thus supporting our findings. Studies have also shown that activation of MAPK pathway (Eralp et al 2008; Gholami et al 2014; Giltnane and Balko 2014; Hashimoto et al 2014; Qi et al 2015; Loi et al 2016) significantly correlates with tumor proliferation and disease progression in TN tumors. MAPK pathway is a sequentially activated cascade consisting of key genes such as Ras, Raf, MEK, and ERK.…”