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

Pon, Cindy K; Lane, J Robert; Sloan, Erica K; Halls, Michelle L

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.-Pon, C. K., Lane, J. R., Sloan, E. K., Halls, M. L. The β2-adrenoceptor activates a positive cAMP-calcium feedforward loop to drive breast cancer cell invasion.

Citation

Pon, C. K., Lane, J. R., Sloan, E. K., & Halls, M. L. (2016). The β2-adrenoceptor activates a positive cAMP-calcium feedforward loop to drive breast cancer cell invasion. FASEB Journal, 30(3), 1144-1154. https://doi.org/10.1096/fj.15-277798

• Journal Article Type: Article
• Acceptance Date: Nov 9, 2015
• Online Publication Date: Nov 17, 2015
• Publication Date: 2016-03
• Deposit Date: Apr 22, 2020
• Journal: FASEB Journal
• Print ISSN: 0892-6638
• Electronic ISSN: 1530-6860
• Publisher: Federation of American Society of Experimental Biology (FASEB)
• Peer Reviewed: Peer Reviewed
• Volume: 30
• Issue: 3
• Pages: 1144-1154
• DOI: https://doi.org/10.1096/fj.15-277798
• Public URL: https://nottingham-repository.worktribe.com/output/1339597
• Publisher URL: https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.15-277798