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

In response to recent studies, we investigated an association between perioperative beta-blockade and breast cancer metastases. First, a retrospective study examining perioperative beta-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 beta 2-activation and inhibition. We also investigated in vivo the metastatic potential of propranolol-treated metastatic cells. For stage II breast cancer patients, perioperative beta-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 beta 2-adrenergic receptor mRNA and protein expression relative to TN primary cells. In response to beta 2-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 beta 2-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 beta 2-activation may promote the establishment of brain metastases of TN breast cancer cells. In addition, our data suggest a benefit to perioperative beta-blockade during surgery-induced stress with respect to breast cancer recurrence and metastases.