Beta-Adrenergic Agonist Reduces the Deformability of Human Breast Cancer Cells

Abstract

Despite significant advancements in diagnosis, therapy, and prevention of breast cancer, metastasis still causes more than 0.5 million deaths every year. Deeper insights into the molecular basis of metastatic traits are crucial to manage metastasis, and to ultimately cure breast cancer. One emerging factor that contributes to disease spread in breast cancer patients is activation of β-adrenergic signaling, which occurs under psychological/emotional stress.Retrospective studies show that exposure to β-adrenergic antagonist drugs (beta blockers) correlates with improved survival of breast cancer patients. An orthotopic mouse model also shows activation of β-adrenoreceptors with either isoproterenol or repeated stress results in increased breast cancer metastasis. While previous studies have investigated the effect of β-adrenergic signaling on the tumor microenvironment, little is known about the physical mechanisms underlying the regulation of metastasis by β-adrenergic signaling. Ultimately disease spread occurs at the single cell level, and their physical properties are critical.Here we investigate how pharmacologic β-adrenergic activation affects the structure, deformability, and migration behavior of breast cancer cells. We treat a metastatic variant of MDA-MB-231 cells with β-adrenergic agonist. We determine changes in subcellular structure by immunofluorescence and quantitative image analysis, and measure cell deformability using parallel microfiltration.β-adrenoreceptor activation by isoproterenol decreases cell deformability significantly. We observe that treatment with isoproterenol increases elongated protrusions and alters the distribution of cytoplasmic F-actin, suggesting that changes in F-actin polymerization may contribute to decreased deformability.Our observations warrant further in vitro and in vivo investigation of the underlying mechanisms by which β-adrenoreceptor activation mediates changes in the biophysical properties of breast cancer cells and consequently regulates metastasis of the disease. Identifying the molecular pathways that are implicated in β-adrenergic signaling-induced changes of cell deformability will inform additional strategies for antimetastatic therapies of primary breast cancers.