Mechanisms Supporting the Use of Beta-Blockers for the Management of Breast Cancer Bone Metastasis

SIMPLE SUMMARY: Bone represents the most common site of metastasis for breast cancer and the establishment and growth of metastatic cancer cells within the skeleton significantly reduces the quality of life of patients and their survival. The interplay between sympathetic nerves and bone cells, and its influence on the process of breast cancer bone metastasis is increasingly being recognized. Several mechanisms, all dependent on β-adrenergic receptor signaling in stromal bone cells, were shown to promote the establishment of disseminated cancer cells into the skeleton. This review provides a summary of these mechanisms in support of the therapeutic potential of β-blockers for the early management of breast cancer metastasis. ABSTRACT: The skeleton is heavily innervated by sympathetic nerves and represents a common site for breast cancer metastases, the latter being the main cause of morbidity and mortality in breast cancer patients. Progression and recurrence of breast cancer, as well as decreased overall survival in breast cancer patients, are associated with chronic stress, a condition known to stimulate sympathetic nerve outflow. Preclinical studies have demonstrated that sympathetic stimulation of β-adrenergic receptors in osteoblasts increases bone vascular density, adhesion of metastatic cancer cells to blood vessels, and their colonization of the bone microenvironment, whereas β-blockade prevented these events in mice with high endogenous sympathetic activity. These findings in preclinical models, along with clinical data from breast cancer patients receiving β-blockers, support the pathophysiological role of excess sympathetic nervous system activity in the formation of bone metastases, and the potential of commonly used, safe, and low-cost β-blockers as adjuvant therapy to improve the prognosis of bone metastases.