Activation of β-adrenoceptor (β-AR) signalling by chronic stress induces metastasis from primary tumours to the lung and lymph nodes in vivo, an effect which is blocked by β-AR antagonists1. In support of this, recent clinical studies found an association between use of β-AR antagonists and reduced distant metastasis in women with triple negative breast cancer2,3. Whilst this suggests that β-blockers may have potential as adjuvant therapy to slow breast cancer progression, how activation of β-AR signalling leads to increased metastasis is not well characterised. The aim of this study was to identify the signalling pathways involved in β-AR potentiation of breast cancer cell invasion. MDA-MB-231 human breast cancer cells were treated with non-selective, β1-AR or β2-AR selective agonists and population based signalling assays were performed to monitor changes to calcium mobilisation, pERK1/2 and cAMP levels in the cells. Non-selective (adrenaline and noradrenaline) and β2-AR selective (formoterol, salbutamol and salmeterol) agonists but not β1-AR selective agonists (xamoterol and RO363) induced cAMP production and inhibited phosphorylation of ERK1/2 in MDA-MB-231 cells. Formoterol, adrenaline and noradrenaline also increased calcium mobilisation. To determine which subtype of β-AR was mediating such effects, the adrenaline and formoterol-induced changes in cAMP and pERK1/2 were further characterised by Schild analysis using β1-AR selective and β2-AR selective antagonists. We found that both agonists signal through β2-AR. Using inhibitors of cAMP and calcium signalling, we identified that these signalling events are interdependent in response to β2-AR stimulation. We also found that formoterol mimicked the effects of stress on breast cancer metastasis in vivo. Interestingly, tumour cells isolated from formoterol treated mice were more invasive than cells from control mice. This suggests an important role for β2-AR signalling in promoting breast cancer invasion and metastasis.
1 Sloan E et al (2010) Cancer Res 70: 7042-7052
2 Botteri E et al (2013) Breast Can Res Treat 140: 567-575
3 Melhem-Bertrandt et al (2011) J Clin Oncol 29(19): 2645-52