Inhibition of β2-Adrenergic Receptor Reduces Triple-Negative Breast Cancer Brain Metastases: The Potential Benefit of Perioperative β-Blockade.

While we look to invent new medicines to treat cancer, a parallel approach to repurpose existing medicines may be highly effective. Stress, mediated by adrenaline, has been suspected to promote cancer growth and this research study shows that by blocking adrenaline receptors in breast cancers, they are less successful in spreading to and growing in the brain.

Background: Cancer cells are under the relentless drive to spread, this metastasis is responsible for a majority of cancer-related deaths. The most ominous part of the body to which cancer can spread is the brain leading to what is called brain metastasis. Because the brain is highly unique in its anatomy and biology, breast cancer cells circulating in the blood would need to exhibit unique features to exploit the brain’s native nutrient sources – neurochemicals. Interestingly, adrenaline is a major neurochemical that is abundant during stress and also narrows blood vessels resulting in elevated blood pressure. Since many people are on regular blood pressure medicine, we investigated with bioinformatics whether patients on beta blockers (a specific blood pressure medicine that blocks the adrenaline receptor) had fewer metastases using a City of Hope patient database. In parallel, we looked at the cancer biology of triple negative breast cancers and adrenaline in the laboratory.

How the Study Was Conducted and Results: This study was initiated by a retrospective study of the metastatic breast cancer patient population at City of Hope, comparing patients who were on beta-blockers versus patients who were not taking beta-blockers. The clinical analysis suggested that there was decreased metastasis in patients taking beta-blockers.

We further investigated the effects of beta-blockers in the laboratory, and found high receptor expression in both Triple Negative (TN) breast cancer and brain metastasis tissues but not in Her2+ breast cancer and brain metastasis tissues. We then applied a variety of beta-blockers used in the clinic to the breast cancer and brain metastasis cells in the laboratory in order to observe three traits of metastasis- proliferation, migration, and invasion. We found that brain metastases cells were more sensitive than primary breast cancer cells to select beta-blocker treatments. There was a decrease in proliferation, migration, and invasion in brain metastasis cells when treated with beta-blockers. Finally, addition to using the beta-blockers alone, we added beta-blockers to cells treated with drugs that would activate the receptor. Although activating the receptor increased metastatic traits, beta-blockers decreased those effects.