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

Abstract

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.

The impact of melatonin and carbon ion irradiation on cancer stem cells

“…No matter what the therapeutic intervention, however, HNSCC is still associated with a high rate of recurrence [113,114]. In addition, metastatic disease remains the principal cause of death in cancer [115,116]. Cell migration and invasion are fundamental steps of the metastatic phenomenon [117,118].…”

β‑blockers inhibit the viability of breast cancer cells by regulating the ERK/COX‑2 signaling pathway and the drug response is affected by ADRB2 single‑nucleotide polymorphisms

“…Işeri et al (24) identified that propranolol and ICI 118,551 (selective β 2 -blockers) inhibited the invasion and migration of non-stimulated breast cancer cells (MCF-7) in vitro. In addition, Choy et al (25) demonstrated that propranolol treatment of triple-negative brain-metastatic cells (MDA-MB-231 Br) decreased the development of brain metastases in vivo. β-blockers have been identified to be beneficial to the survival of patients with TNBC; however, the antitumor mechanism involved remains unclear.…”

Label-Free Dynamic Mass Redistribution Reveals Low-Density, Prosurvival α1B-Adrenergic Receptors in Human SW480 Colon Carcinoma Cells

“…Epidemiologic data compiled from breast cancer outcomes of patients on chronic b-blocker therapy had a 57% reduced risk of metastasis and 71% reduction in mortality after 10 years (Powe et al, 2010). A subsequent study discovered brain metastasis derived from breast cancer cells have increased b2-AR mRNA and protein expression levels, and exhibit enhanced cell proliferation and migration (Choy et al, 2016). Chronic b-AR activation induced by stress promotes colon cancer metastasis (Zhao et al, 2015), possibly through transactivation of the epidermal growth factor receptor-Akt/ extracellular signal-regulated kinase pathway (Chin et al, 2016).…”