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

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Abstract

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 β2-AR-selective agonist terbutaline and the endogenous neurotransmitter norepinephrine decreased VEGF production by MB-231, but increased VEGF production by MB-231BR. Moreover, β2-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.

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Abbreviations

β-AR:

Beta-adrenergic receptor(s)

cAMP:

3′,5′-Cyclic adenosine monophosphate

HBSS:

Hank’s balanced salt solution

BSA:

Bovine serum albumin

FCS:

Fetal calf serum

IBMX:

Isobutylmethylxanthine

ICI:

ICI 118,551 hydrochloride

125ICYP:

125I-cyanopindolol

IL-6:

Interleukin 6

ISO:

Isoproterenol

NE:

Norepinephrine

PKA:

Protein kinase A

TERB:

Terbutaline

VEGF:

Vascular endothelial growth factor

ANOVA:

Analysis of variance

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Acknowledgments

This work was supported by Department of Defense IDEA Award (W81XWH-10-01-008), National Institutes of Health (1 R21 CA152777-01), and by the Breast Cancer Coalition of Rochester to KSM, Department of Defense Era of Hope Scholar Research Award (W81XWH-09-1-0405), National Institutes of Health Director’s New Innovator Award (1 DP2 OD006501-01), and Pew Scholar in the Biomedical Sciences Award to EBB, and Department of Defense Predoctoral Training Award (W81XWH-10-1-0058) to MJS. MJS is a trainee in the Medical Scientist Training Program funded by NIH T32 GM07356. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or National Institutes of Health. We thank Kathryn Fitzgerald, Khawarl Liverpool, and Michael Storonsky for their excellent technical assistance.

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Authors and Affiliations

  1. Department of Biomedical Engineering, University of Rochester Medical Center, Goergen Hall, RC Box 270168, Rochester, NY, 14627, USA

    Kelley S. Madden & Edward B. Brown

  2. Department of Pathology, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY, 14642, USA

    Mercedes J. Szpunar

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  1. Kelley S. Madden
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Correspondence to Kelley S. Madden.

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Madden, K.S., Szpunar, M.J. & Brown, E.B. β-Adrenergic receptors (β-AR) regulate VEGF and IL-6 production by divergent pathways in high β-AR-expressing breast cancer cell lines. Breast Cancer Res Treat 130, 747–758 (2011). https://doi.org/10.1007/s10549-011-1348-y

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