Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer.

Citation data:

Oncotarget, ISSN: 1949-2553, Vol: 8, Issue: 4, Page: 6446-6460

Publication Year:
2017
Captures 17
Readers 17
Citations 6
Citation Indexes 6
PMID:
28031536; 26372813
DOI:
10.18632/oncotarget.14119; 10.18632/oncotarget.5153
PMCID:
PMC4741611
Author(s):
Montoya, Alexa; Amaya, Clarissa N; Belmont, Andres; Diab, Nabih; Trevino, Richard; Villanueva, Geri; Rains, Steven; Sanchez, Luis A; Badri, Nabeel; Otoukesh, Salman; Khammanivong, Ali; Liss, Danielle; Baca, Sarah T; Aguilera, Renato J; Dickerson, Erin B; Torabi, Alireza; Dwivedi, Alok K; Abbas, Aamer; Chambers, Karinn; Bryan, Brad A; Nahleh, Zeina Show More Hide
Publisher(s):
Impact Journals, LLC
Tags:
Medicine
article description
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.