Breast Cancer Research and Treatment

, Volume 130, Issue 3, pp 747–758

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

  • Kelley S. Madden
  • Mercedes J. Szpunar
  • Edward B. Brown
Preclinical study

DOI: 10.1007/s10549-011-1348-y

Cite this article as:
Madden, K.S., Szpunar, M.J. & Brown, E.B. Breast Cancer Res Treat (2011) 130: 747. doi:10.1007/s10549-011-1348-y

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.

Keywords

Breast cancerβ-Adrenergic receptorsVEGFIL-6NorepinephrinecAMP

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

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Kelley S. Madden
    • 1
  • Mercedes J. Szpunar
    • 2
  • Edward B. Brown
    • 1
  1. 1.Department of Biomedical EngineeringUniversity of Rochester Medical CenterRochesterUSA
  2. 2.Department of PathologyUniversity of Rochester Medical CenterRochesterUSA