The β2-adrenoceptor activates a positive cAMP-calcium feedforward loop to drive breast cancer cell invasion

Activation of the sympathetic nervous system by stress increases breast cancer metastasis in vivo. Preclinical studies suggest that stress activates beta-adrenoceptors (beta ARs) to enhance metastasis from primary tumors and that beta-blockers may be protective in breast cancer. However, the subtype of beta AR that mediates this effect, as well as the signaling mechanisms underlying increased tumor cell dissemination, remain unclear. We show that the beta(2)AR is the only functionally relevant beta AR subtype in the highly metastatic human breast cancer cell line MDA-MB-231HM. beta(2)AR activation results in elevated cAMP (formoterol pEC(50) 9.86 +/- 0.32), increased intracellular Ca2+ (formoterol pEC(50) 8.20 +/- 0.33) and reduced phosphorylated ERK (pERK; formoterol pIC(50) 11.62 +/- 0.31). We demonstrate that a highly amplified positive feedforward loop between the cAMP and Ca2+ pathways is responsible for efficient inhibition of basal pERK. Importantly, activation of the beta(2)AR increased invasion (formoterol area under the curve [AUC] relative to vehicle: 1.82 +/- 0.36), which was dependent on the cAMP/Ca2+ loop (formoterol AUC in the presence of 2'5'-dideoxyadenosine 0.64 +/- 0.03, or BAPTA-AM 0.45 +/- 0.23) but independent of inhibition of basal pERK1/2 (vehicle AUC with U0126 0.60 +/- 0.30). Specifically targeting the positive feedforward cAMP/Ca2+ loop may be beneficial for the development of therapeutics to slow disease progression in patients with breast cancer.