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

Alexa Montoya, Clarissa N. Amaya, Andres Belmont, Nabih Diab, Richard Trevino, Geri Villanueva, Steven Rains, Luis A. Sanchez, Nabeel Badri, Salman Otoukesh, Ali Khammanivong, Danielle Liss, Sarah T. Baca, Renato J. Aguilera, Erin B. Dickerson, Alireza Torabi, Alok K. Dwivedi, Aamer Abbas, Karinn Chambers, Brad A. BryanZeina Nahleh

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

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 nonselective β-blockers in patients with early stage breast cancer may lead to decreased tumor proliferation.

Original languageEnglish (US)
Pages (from-to)6446-6460
Number of pages15
JournalOncotarget
Volume8
Issue number4
DOIs
StatePublished - 2017

Bibliographical note

Funding Information:
We would like to thank Dolores Diaz and Jaime Rios (Texas Tech University Health Sciences Center Histology Core Facility) for their assistance with immunohistochemistry. This project was supported by grants to ZN (CPRIT RP120528), ZN and BAB (TTUHSC-El Paso seed grant #533701), and RJA (NIGMS 1SC3GM103713-2; NIMDH 5G12MD007592-22).

Keywords

  • Beta blocker
  • Breast cancer
  • Ki-67
  • Proliferation
  • Propranolol

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