Inhibition of β2-adrenergic receptor reduces triple-negative breast cancer brain metastases: The potential benefit of perioperative β-blockade

Oncol Rep. 2016 Jun;35(6):3135-42. doi: 10.3892/or.2016.4710. Epub 2016 Mar 28.


In response to recent studies, we investigated an association between perioperative β-blockade and breast cancer metastases. First, a retrospective study examining perioperative β-blocker use and cancer recurrence and metastases was conducted on 1,029 patients who underwent breast cancer surgery at the City of Hope Cancer Center between 2000 and 2010. We followed the clinical study and examined proliferation, migration, and invasion in vitro of primary and brain-metastatic breast cancer cells in response to β2-activation and inhibition. We also investigated in vivo the metastatic potential of propranolol-treated metastatic cells. For stage II breast cancer patients, perioperative β-blockade was associated with decreased cancer recurrence using Cox regression analysis (hazard's ratio =0.51; 95% CI: 0.23-0.97; p=0.041). Triple-negative (TN) brain-metastatic cells were found to have increased β2-adrenergic receptor mRNA and protein expression relative to TN primary cells. In response to β2-adrenergic receptor activation, TN brain-metastatic cells also exhibited increased cell proliferation and migration relative to the control. These effects were abrogated by propranolol. Propranolol decreased β2-adrenergic receptor-activated invasion. In vivo, propranolol treatment of TN brain-metastatic cells decreased establishment of brain metastases. Our results suggest that stress and corresponding β2-activation may promote the establishment of brain metastases of TN breast cancer cells. In addition, our data suggest a benefit to perioperative β-blockade during surgery-induced stress with respect to breast cancer recurrence and metastases.

MeSH terms

  • Adrenergic beta-2 Receptor Antagonists / pharmacology*
  • Adrenergic beta-2 Receptor Antagonists / therapeutic use
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / mortality
  • Brain Neoplasms / prevention & control*
  • Brain Neoplasms / secondary
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Combined Modality Therapy
  • Disease-Free Survival
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Mice, Inbred NOD
  • Mice, SCID
  • Middle Aged
  • Neoplasm Recurrence, Local / metabolism
  • Neoplasm Recurrence, Local / mortality
  • Neoplasm Recurrence, Local / prevention & control*
  • Perioperative Period
  • Proportional Hazards Models
  • Propranolol / pharmacology*
  • Propranolol / therapeutic use
  • Receptors, Adrenergic, beta-2 / metabolism
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / mortality
  • Triple Negative Breast Neoplasms / pathology
  • Xenograft Model Antitumor Assays
  • Young Adult


  • ADRB2 protein, human
  • Adrenergic beta-2 Receptor Antagonists
  • Receptors, Adrenergic, beta-2
  • Propranolol