Differential β₂-adrenergic receptor expression defines the phenotype of non-tumorigenic and malignant human breast cell lines.

Lucía Gargiulo,Isabel A Lüthy,Céline Galés,Ezequiel M Rivero,Sabrina Copsel,Carlos Davio,Ariana Bruzzone,Jean-Michel Sénard

doi:10.18632/oncotarget.2460

Abstract

Breast cancer is the most frequent malignancy in women. Several reports demonstrated that adrenergic receptors (ARs) are involved in breast cancer. Here we observed that epinephrine (Epi), an endogenous AR agonist, caused opposite effects in non-tumorigenic (MCF-10A and HBL-100) and tumor cells (MCF-7 and MDA-MB-231). Thus, Epi, in non-tumor breast cells, as well as isoproterenol (β-agonist), in all cell lines, maintained a benign phenotype, decreasing cell proliferation and migration, and stimulating cell adhesion. β-AR expression and cAMP levels were higher in MCF-10A than in MCF-7 cells. β₂-AR knock-down caused a significant increase of cell proliferation and migration, and a decrease of cell adhesion both in basal and in Iso-stimulated conditions. Coincidently, β₂-AR over-expression induced a significant decrease of cell proliferation and migration, and an increase of cell adhesion. Therefore, β₂-AR is implied in cell phenotype and its agonists or antagonists could eventually complement cancer therapy.

Highlights

Breast cancer is the most frequent malignancy in women worldwide, accounting for 23% of cancers in women, and the main cause of cancer death in women in both developing and developed countries
The stimulation of β2-adrenergic receptors (ARs) leads to Gs-dependent adenylyl cyclase activation and cAMP production which activates protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac)
As epinephrine (Epi) is the endogenous AR ligand that binds to all ARs, we assessed its action on different parameters linked to breast cancer progression, such as proliferation, adhesion and migration

Summary

Introduction

Breast cancer is the most frequent malignancy in women worldwide, accounting for 23% of cancers in women, and the main cause of cancer death in women in both developing and developed countries. The molecular profiling of different subtypes of breast cancer greatly improved treatments and outcomes for patients [3]. Epinephrine (Epi, known as adrenaline) and Norepinephrine (NEpi, or noradrenaline) are classic neurotransmitters that mediate stress responses from the autonomic nervous system (a mechanism usually stated as “fight or flight” response). These catecholamines bind to three types of adrenergic receptors (ARs), subdivided in 9 different subtypes: α1A, α1B, α1D, α2A, α2B, α2C, β1, β2, β3 [5]. Desensitization of β2-AR is mediated by GPCR kinase-dependent phosphorylation, followed by the recruitment of β-arrestins, independent signal transducers [6]

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