The beta adrenergic receptor antagonist propranolol alters mitogenic and apoptotic signaling in late stage breast cancer

Abstract

BackgroundSubstantial evidence supports the use of inexpensive β-AR antagonists (beta blockers) against a variety of cancers, and the β-AR antagonist propranolol was recently approved by the European Medicines Agency for the treatment of soft tissue sarcomas. Prospective and retrospective data published by our group and others suggest that non-selective β-AR antagonists are effective at reducing proliferative rates in breast cancers, however the mechanism by which this occurs is largely unknown. MethodsIn this study, we measured changes in tumor proliferation and apoptosis in a late stage breast cancer patient treated with neoadjuvant propranolol. We expounded upon these clinical findings by employing an in vitro breast cancer model, where we used cell-based assays to evaluate propranolol-mediated molecular alterations related to cell proliferation and apoptosis. ResultsNeoadjuvant propranolol decreased expression of the pro-proliferative Ki-67 and pro-survival Bcl-2 markers, and increased pro-apoptotic p53 expression in a patient with stage III breast cancer. Molecular analysis revealed that β-AR antagonism disrupted cell cycle progression and steady state levels of cyclins. Furthermore, propranolol treatment of breast cancer cells increased p53 levels, enhanced caspase cleavage, and induced apoptosis. ConclusionCollectively, these data provide support for the incorporation of β-AR antagonists into the clinical management of breast cancer, and elucidate a partial molecular mechanism explaining the efficacy of β-AR antagonists against this disease.