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

摘要: Activation of the sympathetic nervous system by stress increases breast cancer metastasis in vivo. Preclinical studies suggest that activates β-adrenoceptors (βARs) to enhance from primary tumors and β-blockers may be protective cancer. However, subtype βAR mediates this effect, as well signaling mechanisms underlying increased tumor cell dissemination, remain unclear. We show β2AR is only functionally relevant highly metastatic human line MDA-MB-231HM. activation results elevated cAMP (formoterol pEC50 9.86 ± 0.32), intracellular Ca(2+) 8.20 0.33) reduced phosphorylated ERK (pERK; formoterol pIC50 11.62 0.31). demonstrate a amplified positive feedforward loop between pathways responsible for efficient inhibition basal pERK. Importantly, invasion area under curve [AUC] relative vehicle: 1.82 0.36), which was dependent on cAMP/Ca(2+) AUC presence 2'5'-dideoxyadenosine 0.64 0.03, or BAPTA-AM 0.45 0.23) but independent pERK1/2 (vehicle with U0126 0.60 0.30). Specifically targeting beneficial development therapeutics slow disease progression patients