β-Adrenergic receptors (β-AR) regulate VEGF and IL-6 production by divergent pathways in high β-AR-expressing breast cancer cell lines

Activation of beta-adrenergic receptors (beta-AR) drives proangiogenic factor production in several types of cancers. To examine beta-AR regulation of breast cancer pathogenesis, beta-AR density, signaling capacity, and functional responses to beta-AR stimulation were studied in four human breast adenocarcinoma cell lines. beta-AR density ranged from very low in MCF7 and MB-361 to very high in MB-231 and in a brain-seeking variant of MB-231, MB-231BR. Consistent with beta-AR density, beta-AR activation elevated cAMP in MCF7 and MB-361 much less than in MB-231 and MB-231BR. Functionally, beta-AR stimulation did not markedly alter vascular endothelial growth factor (VEGF) production by MCF7 or MB-361. In the two high beta-AR-expressing cell lines MB-231 and MB-231BR, beta-AR-induced cAMP and VEGF production differed considerably, despite similar beta-AR density. The beta(2)-AR-selective agonist terbutaline and the endogenous neurotransmitter norepinephrine decreased VEGF production by MB-231, but increased VEGF production by MB-231BR. Moreover, beta(2)-AR activation increased IL-6 production by both MB-231 and MB-231BR. These functional alterations were driven by elevated cAMP, as direct activation of adenylate cyclase by forskolin elicited similar alterations in VEGF and IL-6 production. The protein kinase A antagonist KT5720 prevented beta-AR-induced alterations in MB-231 and MB-231BR VEGF production, but not IL-6 production. Conclusions beta-AR expression and signaling is heterogeneous in human breast cancer cell lines. In cells with high beta-AR density, beta-AR stimulation regulates VEGF production through the classical beta-AR-cAMP-PKA pathway, but this pathway can elicit directionally opposite outcomes. Furthermore, in the same cells, beta-AR activate a cAMP-dependent, PKA-independent pathway to increase IL-6 production. The complexity of breast cancer cell beta-AR expression and functional responses must be taken into account when considering beta-AR as a therapeutic target for breast cancer treatment.