The β2-adrenergic receptor and Her2 comprise a positive feedback loop in human breast cancer cells
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In this study, β2-AR level was found to be up-regulated in MCF-7 cells overexpressing Her2 (MCF-7/Her2). Correlation of β2-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. β2-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 β2-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 β2-AR and Her2 comprise a positive feedback loop in human breast cancer cells.
Keywordsβ2-AR Her2 STAT3 ERK Breast cancer
We are very grateful to Drs. Bromber and Darnell for providing STAT3-dominant negative construct. This study is supported by the National Basic Research Program of China (973 Program, No. 2006CB504305 and 2010CB911904), the National High-Tech Research and Development Plan (863 Program, No. 2006AA02A245), the National Key Technologies R&D Program for New Drugs (2008ZX10004-015, 2009ZX09301-002, and 2009ZX09103-619), the Grand Science and Technology Special Program concerning prevention and treatment of infectious diseases (2008ZX10004-015), and the National Natural Science Foundation of China (No. 30771981, 30901766, and 30972690).