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.

β‑blockers inhibit the viability of breast cancer cells by regulating the ERK/COX‑2 signaling pathway and the drug response is affected by ADRB2 single‑nucleotide polymorphisms

“…However, propranolol (a non-selective β-blocker) was identified to be effective in treating severe infantile hemangiomas and has been approved as the first-line therapy for proliferating infantile hemangioma by the US Food and Drug Administration in 2014 (16). A number of in vitro and in vivo studies have also demonstrated the antitumor activity of β-blockers against various types of cancer, including breast (17,18), pancreatic (19) and prostate cancer (20), and ovarian carcinomas (21), melanoma (22) and neuroblastoma (23). Işeri et al (24) identified that propranolol and ICI 118,551 (selective β 2 -blockers) inhibited the invasion and migration of non-stimulated breast cancer cells (MCF-7) in vitro.…”

β-Adrenoceptor Blockade for Infantile Hemangioma Therapy: Do β₃-Adrenoceptors Play a Role?

“…Similarly, Montoya et al [100] demonstrated that selective β 1 -adrenoceptor antagonist therapies were less effective against proliferation of tumors than nonselective ones. The above lines of evidence, in a simplistic interpretation, may be explained in 2 main ways: (1) it is mandatory to induce the blockade of more than one β-adrenoceptor type, and/or (2) β 1 -adrenoceptor blockade alone is not responsible for the therapeutic effects in these cases.…”

The ABC7 regimen: a new approach to metastatic breast cancer using seven common drugs to inhibit epithelial-to-mesenchymal transition and augment capecitabine efficacy

“…A single ER+, HER2− patient was treated with 25 days of propranolol 1.5 mg/kg per day after diagnostic biopsy but before resection. Resection of tumor tissue showed a 23% reduction in Ki67 staining compared to biopsy tissue 25 days earlier, before any propranolol 185. Of important note, beta-1-selective beta-blockers did not work to reduce Ki67, only nonselective beta-blockers did.…”