Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer
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Alexa Montoya1,2,*, Clarissa N. Amaya1,*, Andres Belmont3,*, Nabih Diab3, Richard Trevino3, Geri Villanueva3, Steven Rains1, Luis A. Sanchez4, Nabeel Badri4, Salman Otoukesh4, Ali Khammanivong5, Danielle Liss4, Sarah T. Baca6, Renato J. Aguilera6, Erin B. Dickerson5,7, Alireza Torabi3,8, Alok K. Dwivedi1,3,9, Aamer Abbas3,4, Karinn Chambers3,10, Brad A. Bryan1,3, Zeina Nahleh3,4
1Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, Texas, USA
2Department of Biology, University of Texas, El Paso, Texas, USA
3Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA
4Department of Hematology/Oncology, Loma Linda University Health Sciences Center, Loma Linda, California, USA
5Department of Veterinary Clinical Sciences, University of Minnesota, Saint Paul, Minnesota, USA
6Border Biomedical Research Center, University of Texas, El Paso, Texas, USA
7Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
8Department of Pathology, Texas Tech University Health Sciences Center, El Paso, Texas, USA
9Division of Biostatistics and Epidemiology, Texas Tech University Health Sciences Center, El Paso, Texas, USA
10Department of Surgery, Texas Tech University Health Sciences Center, El Paso, Texas, USA
*These authors contributed equally to this work
Zeina Nahleh, email: [email protected]
Brad A. Bryan, email: [email protected]
Keywords: beta blocker, propranolol, breast cancer, proliferation, Ki-67
Received: September 07, 2016 Accepted: December 13, 2016 Published: December 23, 2016
Previous studies suggest beta-adrenergic receptor (β-AR) antagonists (β-blockers) decrease breast cancer progression, tumor metastasis, and patient mortality; however the mechanism for this is unknown. Immunohistochemical analysis of normal and malignant breast tissue revealed overexpression of β1-AR and β3-AR in breast cancer. A retrospective cross-sectional study of 404 breast cancer patients was performed to determine the effect of β-blocker usage on tumor proliferation. Our analysis revealed that non-selective β-blockers, but not selective β-blockers, reduced tumor proliferation by 66% (p < 0.0001) in early stage breast cancer compared to non-users. We tested the efficacy of propranolol on an early stage breast cancer patient, and quantified the tumor proliferative index before and after treatment, revealing a propranolol-mediated 23% reduction (p = 0.02) in Ki67 positive tumor cells over a three-week period. The anti-proliferative effects of β-blockers were measured in a panel of breast cancer lines, demonstrating that mammary epithelial cells were resistant to propranolol, and that most breast cancer cell lines displayed dose dependent viability decreases following treatment. Selective β-blockers alone or in combination were not as effective as propranolol at reducing breast cancer cell proliferation. Molecular analysis revealed that propranolol treatment of the SK-BR-3 breast cancer line, which showed high sensitivity to beta blockade, led to a reduction in Ki67 protein expression, decreased phosphorylation of the mitogenic signaling regulators p44/42 MAPK, p38 MAPK, JNK, and CREB, increased phosphorylation of the cell survival/apoptosis regulators AKT, p53, and GSK3β. In conclusion, use of non-selective β-blockers in patients with early stage breast cancer may lead to decreased tumor proliferation.
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