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

Activation of b-adrenergic receptors (b-AR) drives proangiogenic factor production in several types of cancers. To examine b-AR regulation of breast cancer pathogenesis, b-AR density, signaling capacity, and functional responses to b-AR stimulation were studied in four human breast adenocarcinoma cell lines. b-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 b-AR density, b-AR activation elevated cAMP in MCF7 and MB-361 much less than in MB-231 and MB-231BR. Functionally, b-AR stimulation did not markedly alter vascular endothelial growth factor (VEGF) production by MCF7 or MB-361. In the two high b-AR-expressing cell lines MB-231 and MB-231BR, b-AR-induced cAMP and VEGF production differed considerably, despite similar b-AR density. The b2-ARselective agonist terbutaline and the endogenous neurotransmitter norepinephrine decreased VEGF production by MB-231, but increased VEGF production by MB-231BR. Moreover, b2-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 b-AR-induced alterations in MB-231 and MB-231BR VEGF production, but not IL-6 production. Conclusions b-AR expression and signaling is heterogeneous in human breast cancer cell lines. In cells with high b-AR density, b-AR stimulation regulates VEGF production through the classical b-AR-cAMP-PKA pathway, but this pathway can elicit directionally opposite outcomes. Furthermore, in the same cells, b-AR activate a cAMP-dependent, PKA-independent pathway to increase IL-6 production. The complexity of breast cancer cell b-AR expression and functional responses must be taken into account when considering b-AR as a therapeutic target for breast cancer treatment.