title: The β2-adrenoceptor activates a positive cAMP-calcium feedforward loop to drive breast cancer cell invasion.
abstract: Activation of the sympathetic nervous system by stress increases breast cancer metastasis in vivo. Preclinical studies suggest that stress activates β-adrenoceptors (βARs) to enhance metastasis from primary tumors and that β-blockers may be protective in breast cancer. However, the subtype of βAR that mediates this effect, as well as the signaling mechanisms underlying increased tumor cell dissemination, remain unclear. We show that the β2AR is the only functionally relevant βAR subtype in the highly metastatic human breast cancer cell line MDA-MB-231HM. β2AR activation results in elevated cAMP (formoterol pEC50 9.86 ± 0.32), increased intracellular Ca(2+) (formoterol pEC50 8.20 ± 0.33) and reduced phosphorylated ERK (pERK; formoterol pIC50 11.62 ± 0.31). We demonstrate that a highly amplified positive feedforward loop between the cAMP and Ca(2+) pathways is responsible for efficient inhibition of basal pERK. Importantly, activation of the β2AR increased invasion (formoterol area under the curve [AUC] relative to vehicle: 1.82 ± 0.36), which was dependent on the cAMP/Ca(2+) 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/Ca(2+) loop may be beneficial for the development of therapeutics to slow disease progression in patients with breast cancer.
authors.affiliation: *Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; Cousins Center, UCLA Semel Institute for Neuroscience and Human Behavior, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California USA; and Division of Cancer Surgery, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Cindy K
authors.initials: CK
authors.lastname: Pon
authors.affiliation: *Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; Cousins Center, UCLA Semel Institute for Neuroscience and Human Behavior, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California USA; and Division of Cancer Surgery, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: J Robert
authors.initials: JR
authors.lastname: Lane
authors.affiliation: *Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; Cousins Center, UCLA Semel Institute for Neuroscience and Human Behavior, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California USA; and Division of Cancer Surgery, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Erica K
authors.initials: EK
authors.lastname: Sloan
authors.affiliation: *Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; Cousins Center, UCLA Semel Institute for Neuroscience and Human Behavior, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California USA; and Division of Cancer Surgery, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia michelle.halls@monash.edu.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Halls
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009361:Neoplasm Invasiveness; D010766:Phosphorylation / Q000187:drug effects; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*
chemical_list: D000319:Adrenergic beta-Antagonists; D018343:Receptors, Adrenergic, beta-2; D000242:Cyclic AMP; D002118:Calcium
keywords: GPCR; adrenergic receptor; metastasis; stress