Journal
BREAST CANCER RESEARCH AND TREATMENT
Volume 125, Issue 2, Pages 351-362Publisher
SPRINGER
DOI: 10.1007/s10549-010-0822-2
Keywords
beta 2-AR; Her2; STAT3; ERK; Breast cancer
Categories
Funding
- National Basic Research Program of China (973 Program) [2006CB504305, 2010CB911904]
- National High-Tech Research and Development Plan (863 Program) [2006AA02A245]
- National Key Technologies R&D Program for New Drugs [2008 ZX10004-015, 2009ZX09301-002, 2009ZX09103-619]
- Grand Science and Technology Special Program concerning prevention and treatment of infectious diseases [2008ZX10004-015]
- National Natural Science Foundation of China [30771981, 30901766, 30972690]
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In this study, beta 2-AR level was found to be up-regulated in MCF-7 cells overexpressing Her2 (MCF-7/Her2). Correlation of beta 2-AR level with Her2 status was demonstrated in breast cancer tissue samples. Constitutive phosphorylation of ERK, mRNA expression up-regulation of catecholamine-synthesis enzymes, and increased epinephrine release were detected in MCF-7/Her2 cells. beta 2-AR expression induced by epinephrine and involvement of ERK signaling were validated. The data indicate that Her2 overexpression and excessive phosphorylation of ERK cause epinephrine autocrine release from breast cancer cells, resulting in up-regulation of beta 2-AR expression. The data also showed that catecholamine prominently stimulated Her2 mRNA expression and promoter activity. The activation and nuclear translocation of STAT3 triggered by isoproterenol were observed. Enhanced binding activities of STAT3 to the Her2 promoter after isoproterenol stimulation were verified. Using STAT3 shRNA and dominant negative STAT3 mutant, the role of STAT3 in isoproterenol-induced Her2 expression was further confirmed. The data support a model where beta 2-AR and Her2 comprise a positive feedback loop in human breast cancer cells.
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