期刊
BREAST CANCER RESEARCH AND TREATMENT
卷 130, 期 3, 页码 747-758出版社
SPRINGER
DOI: 10.1007/s10549-011-1348-y
关键词
Breast cancer; beta-Adrenergic receptors; VEGF; IL-6; Norepinephrine; cAMP
类别
资金
- Department of Defense IDEA [W81XWH-10-01-008]
- National Institutes of Health [1 R21 CA152777-01, 1 DP2 OD006501-01, T32 GM07356]
- Breast Cancer Coalition of Rochester
- Department of Defense [W81XWH-09-1-0405, W81XWH-10-1-0058]
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.
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