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 β-adrenergic receptors (β-AR) drives proangiogenic factor production in several types of cancers. To examine β-AR regulation of breast cancer pathogenesis, β-AR density, signaling capacity, and functional responses to β-AR stimulation were studied in four human breast adenocarcinoma ce...

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Published in:Breast cancer research and treatment 2011-12, Vol.130 (3), p.747-758
Main Authors: Madden, Kelley S., Szpunar, Mercedes J., Brown, Edward B.
Format: Article
Language:English
Subjects:
Adenocarcinoma - metabolism
Biological and medical sciences
Breast cancer
Breast Neoplasms - metabolism
Cell Line, Tumor
Cell Proliferation
Colforsin - pharmacology
Cyclic AMP - biosynthesis
Cyclic AMP - metabolism
Cyclic AMP-Dependent Protein Kinases - metabolism
Female
Gynecology. Andrology. Obstetrics
Humans
Interleukin-6 - biosynthesis
Mammary gland diseases
Medical sciences
Medicine
Medicine & Public Health
Oncology
Preclinical Study
Receptors, Adrenergic, beta - metabolism
Signal Transduction - drug effects
Tumors
Vascular endothelial growth factor
Vascular Endothelial Growth Factor A - biosynthesis
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Summary:Activation of β-adrenergic receptors (β-AR) drives proangiogenic factor production in several types of cancers. To examine β-AR regulation of breast cancer pathogenesis, β-AR density, signaling capacity, and functional responses to β-AR stimulation were studied in four human breast adenocarcinoma cell lines. β-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 β-AR density, β-AR activation elevated cAMP in MCF7 and MB-361 much less than in MB-231 and MB-231BR. Functionally, β-AR stimulation did not markedly alter vascular endothelial growth factor (VEGF) production by MCF7 or MB-361. In the two high β-AR-expressing cell lines MB-231 and MB-231BR, β-AR-induced cAMP and VEGF production differed considerably, despite similar β-AR density. The β 2 -AR-selective agonist terbutaline and the endogenous neurotransmitter norepinephrine decreased VEGF production by MB-231, but increased VEGF production by MB-231BR. Moreover, β 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 β-AR-induced alterations in MB-231 and MB-231BR VEGF production, but not IL-6 production. Conclusions β-AR expression and signaling is heterogeneous in human breast cancer cell lines. In cells with high β-AR density, β-AR stimulation regulates VEGF production through the classical β-AR-cAMP-PKA pathway, but this pathway can elicit directionally opposite outcomes. Furthermore, in the same cells, β-AR activate a cAMP-dependent, PKA-independent pathway to increase IL-6 production. The complexity of breast cancer cell β-AR expression and functional responses must be taken into account when considering β-AR as a therapeutic target for breast cancer treatment.
ISSN:0167-6806
1573-7217
DOI:10.1007/s10549-011-1348-y