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Beta-adrenergic blocking drugs in breast cancer: a perspective review.

ABSTRACT: The purpose of this review is to present the preclinical, epidemiological and clinical data relevant to the association between ?-blockers and breast cancer progression. Preclinical studies have shown that ?-adrenergic receptor (?-AR) signalling can inhibit multiple cellular processes involved in breast cancer progression and metastasis, including extracellular matrix invasion, expression of inflammatory and chemotactic cytokines, angiogenesis and tumour immune responses. This has led to the hypothesis that the commonly prescribed class of ?-AR antagonist drugs (?-blockers) may favourably impact cancer progression. A number of recent pharmacoepidemiological studies have examined the association between ?-blocker exposure and breast cancer progression. The results from these studies have suggested a potential role for targeting the ?-AR pathway in breast cancer patients. Larger observational studies are, however, required to confirm these results. Questions regarding the type of ?-blocker, predictive biomarkers or tumour characteristics, appropriate treatment paradigms and, most importantly, efficacy must also be answered in randomized clinical studies before ?-blockers can be considered a therapeutic option for patients with breast cancer.

SUBMITTER: Barron TI

PROVIDER: S-EPMC3349076 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Beta-adrenergic blocking drugs in breast cancer: a perspective review.

Barron Thomas I TI Sharp Linda L Visvanathan Kala K

Therapeutic advances in medical oncology 20120501 3

The purpose of this review is to present the preclinical, epidemiological and clinical data relevant to the association between β-blockers and breast cancer progression. Preclinical studies have shown that β-adrenergic receptor (β-AR) signalling can inhibit multiple cellular processes involved in breast cancer progression and metastasis, including extracellular matrix invasion, expression of inflammatory and chemotactic cytokines, angiogenesis and tumour immune responses. This has led to the hyp ...[more]

PMID: 22590485

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Project description:IntroductionTumor-associated calcium signal transducer 2 (Trop2) has been used as a transport gate for cytotoxic agents into cells in antibody-drug conjugate designs because of its expression in a wide range of solid tumors. However, the specific role of Trop2 itself in breast cancer progression remains unclear and small molecules targeting Trop2 have not yet been reported.ObjectivesTo screen small molecules targeting Trop2, and to reveal its pharmacological effects and the molecular mechanisms of action.MethodsSmall molecule targeting Trop2 was identified by cell membrane chromatography, and validated by cellular thermal shift assay and point mutation analyses. We investigated the pharmacological effects of Trop2 inhibitor using RNA-seq, human foreskin fibroblast (HFF)-derived extracellular matrix (ECM), Matrigel drop invasion assays, colony-forming assay, xenograft tumor model, 4T1 orthotopic metastasis model and 4T1 experimental metastasis model. The molecular mechanism was determined using immunoprecipitation, mass spectrometry, immunofluorescence, immunohistochemistry and Western blotting.ResultsHere we identified Bruceine D (BD) as the inhibitor of Trop2, and demonstrated anti-metastasis effects of BD in breast cancer. Notably, Lys307 and Glu310 residues of Trop2 acted as critical sites for BD binding. Mechanistically, BD suppressed Trop2-induced cancer metastasis by blocking the formation of Trop2/β-catenin positive loop, in which the Trop2/β-catenin complex prevented β-catenin from being degraded via the ubiquitin-proteosome pathway. Destabilized β-catenin caused by BD reduced nucleus translocation, leading to the reduction of transcription of Trop2, the reversal of epithelial-mesenchymal transition (EMT) process, and the inhibition of ECM remodeling, further inhibiting cancer metastasis. Additionally, the inhibitory effects of BD on lung metastatic colonization and the beneficial effects of BD on prolongation of survival were validated in 4T1 experimental metastasis model.ConclusionsThese results support the tumor-promoting role of Trop2 in breast cancer by stabilizing β-catenin in Trop2/β-catenin positive loop, and suggest Bruceine D as a promising candidate for Trop2 inhibition.

Dataset Information

Beta-adrenergic blocking drugs in breast cancer: a perspective review.

Publications

Beta-adrenergic blocking drugs in breast cancer: a perspective review.

Similar Datasets

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