Chronic stress-associated growth and metastasis of triple-negative breast cancer potentially involves β-adrenergic/p38 MAPK signaling

Chronic stress is known to facilitate the progression of breast cancer. The p38 mitogen-activated protein kinase (p38 MAPK) pathway is involved in multiple stress-related cascade reactions, but its role under chronic stress in triple-negative breast cancer (TNBC) remains unclear. In this study, a nude mice model bearing TNBC was established. Chronic stress was induced via the restraint method, and its effects on epinephrine (E) and norepinephrine (NE) release, tumor growth and metastasis, and p38 MAPK phosphorylation were investigated. In parallel, the effects of E and NE on the proliferation, migration, and p-p38 MAPK levels of TNBC cell lines (MDA-MB-231 and MDA-MB-468) were examined in vitro. In vivo findings revealed that chronic stress promoted TNBC growth and metastasis, increased plasma E and NE levels, and reduced p-p38 MAPK expression. Notably, β₂-AR expression was higher in TNBC tissues than in normal breast tissues, and was also higher in TNBC cells than in normal mammary epithelial cells. In vitro, E and NE enhanced TNBC cell proliferation and migration, suppressed p38 MAPK phosphorylation, and upregulated PCNA and MMP-9. However, Propranolol (Pro) partially attenuated these effects by inhibiting TNBC cell proliferation and migration, restoring p38 MAPK phosphorylation, and decreasing PCNA and MMP-9 levels. These results suggest that chronic stress promotes TNBC progression, potentially involving β-adrenergic/p38 MAPK signaling, and support further investigation of this pathway in chronic stress-associated TNBC progression.