title: Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer.
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 non-selective β-blockers in patients with early stage breast cancer may lead to decreased tumor proliferation.
authors.affiliation: Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, Texas, USA.|Department of Biology, University of Texas, El Paso, Texas, USA.
authors.forename: Alexa
authors.initials: A
authors.lastname: Montoya
authors.affiliation: Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, Texas, USA.
authors.forename: Clarissa N
authors.initials: CN
authors.lastname: Amaya
authors.affiliation: Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Belmont
authors.affiliation: Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA.
authors.forename: Nabih
authors.initials: N
authors.lastname: Diab
authors.affiliation: Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Trevino
authors.affiliation: Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA.
authors.forename: Geri
authors.initials: G
authors.lastname: Villanueva
authors.affiliation: Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, Texas, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Rains
authors.affiliation: Department of Hematology/Oncology, Loma Linda University Health Sciences Center, Loma Linda, California, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Sanchez
authors.affiliation: Department of Hematology/Oncology, Loma Linda University Health Sciences Center, Loma Linda, California, USA.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Badri
authors.affiliation: Department of Hematology/Oncology, Loma Linda University Health Sciences Center, Loma Linda, California, USA.
authors.forename: Salman
authors.initials: S
authors.lastname: Otoukesh
authors.affiliation: Department of Veterinary Clinical Sciences, University of Minnesota, Saint Paul, Minnesota, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Khammanivong
authors.affiliation: Department of Hematology/Oncology, Loma Linda University Health Sciences Center, Loma Linda, California, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Liss
authors.affiliation: Border Biomedical Research Center, University of Texas, El Paso, Texas, USA.
authors.forename: Sarah T
authors.initials: ST
authors.lastname: Baca
authors.affiliation: Border Biomedical Research Center, University of Texas, El Paso, Texas, USA.
authors.forename: Renato J
authors.initials: RJ
authors.lastname: Aguilera
authors.affiliation: Department of Veterinary Clinical Sciences, University of Minnesota, Saint Paul, Minnesota, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Erin B
authors.initials: EB
authors.lastname: Dickerson
authors.affiliation: Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA.|Department of Pathology, Texas Tech University Health Sciences Center, El Paso, Texas, USA.
authors.forename: Alireza
authors.initials: A
authors.lastname: Torabi
authors.affiliation: Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, Texas, USA.|Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA.|Division of Biostatistics and Epidemiology, Texas Tech University Health Sciences Center, El Paso, Texas, USA.
authors.forename: Alok K
authors.initials: AK
authors.lastname: Dwivedi
authors.affiliation: Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA.|Department of Hematology/Oncology, Loma Linda University Health Sciences Center, Loma Linda, California, USA.
authors.forename: Aamer
authors.initials: A
authors.lastname: Abbas
authors.affiliation: Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA.|Department of Surgery, Texas Tech University Health Sciences Center, El Paso, Texas, USA.
authors.forename: Karinn
authors.initials: K
authors.lastname: Chambers
authors.affiliation: Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, Texas, USA.|Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA.
authors.forename: Brad A
authors.initials: BA
authors.lastname: Bryan
authors.affiliation: Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA.|Department of Hematology/Oncology, Loma Linda University Health Sciences Center, Loma Linda, California, USA.
authors.forename: Zeina
authors.initials: Z
authors.lastname: Nahleh
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003430:Cross-Sectional Studies; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009367:Neoplasm Staging; D010766:Phosphorylation; D011433:Propranolol / Q000627:therapeutic use*; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000378:metabolism; D022702:Receptors, Adrenergic, beta-3 / Q000187:drug effects / Q000378:metabolism; D012189:Retrospective Studies; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C547787:ADRB1 protein, human; C568534:ADRB3 protein, human; D000319:Adrenergic beta-Antagonists; D051017:Apoptosis Regulatory Proteins; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D019394:Ki-67 Antigen; D018342:Receptors, Adrenergic, beta-1; D022702:Receptors, Adrenergic, beta-3; D011433:Propranolol; D020928:Mitogen-Activated Protein Kinases
keywords: Ki-67; beta blocker; breast cancer; proliferation; propranolol