Nebivolol-induced bi-directional modulation of intracellular kinases contributes to the inhibition of triple-negative breast cancer.

Stress-induced β-adrenergic signaling is widely recognized as a detrimental factor in breast cancer progression, and β-blockers have been shown to exert beneficial effects on breast cancer patients in various clinical settings. However, the molecular mechanisms underlying these beneficial effects remain incompletely understood, which hampers the clinical application of existing β-blockers and the development of more effective anti-tumor agents targeting β-adrenergic signaling. In this study, we investigated the third-generation β-blocker nebivolol to elucidate how this drug alters the phenotype of triple-negative breast cancer (TNBC) cells by modulating intracellular signaling pathways. We found that nebivolol inhibited TNBC cell proliferation, invasion, and metastasis, effects that were associated with the expression of the β2-adrenergic receptor (β2-AR) on tumor cells. These anti-tumor effects were accompanied by nebivolol-induced apoptosis, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress, as well as alterations in intracellular mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling. Specifically, nebivolol increased the phosphorylation of p38 mitogen-activated protein kinases (p38) and Jun N-terminal kinase (JNK) in TNBC cells, while decreasing extracellular signal-regulated protein kinase 1/2 (ERK1/2) and Akt phosphorylation. Furthermore, inhibition of ERK1/2 or Akt enhanced the suppressive effects of nebivolol on TNBC cell proliferation and migration, whereas inhibition of JNK or p38 attenuated its anti-tumor activity. These findings demonstrate that nebivolol exerts anti-tumor effects on TNBC via deliberate modulation of intracellular signaling pathways in the tumor cells. This study promotes the potential of repurposing β-blockers as anti-cancer therapeutics and highlights the clinical promise of combining them with selective kinase inhibitors.