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Breast Cancer Res Treat (2011) 125:351362 DOI 10.1007/s10549-010-0822-2
PRECLINICAL STUDY
The b2-adrenergic receptor and Her2 comprise a positive feedback loop in human breast cancer cells
Ming Shi Dan Liu Huijun Duan Lu Qian Lina Wang Lijia Niu
Huipeng Zhang Zheng Yong Zehui Gong Lun Song Ming Yu
Meiru Hu Qing Xia Beifen Shen Ning Guo
Received: 19 January 2010 / Accepted: 24 February 2010 / Published online: 17 March 2010 Springer Science+Business Media, LLC. 2010
Abstract In this study, b2-AR level was found to be up-regulated in MCF-7 cells overexpressing Her2 (MCF-7/ Her2). Correlation of b2-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. b2-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 b2-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 veried. Using STAT3 shRNA and dominant negative STAT3 mutant, the role of STAT3 in isoproterenol-induced Her2 expression was further conrmed. The data support a model where b2-AR and
Her2 comprise a positive feedback loop in human breast cancer cells.
Keywords b2-AR Her2 STAT3 ERK Breast cancer
Introduction
b2-adrenergic receptor (b2-AR) is an important member of seven transmembrane G protein-coupled receptors (GPCRs). The traditional functions of GPCR were considered as short-term regulators of intermediary metabolism, exerting the intracellular effects through a classic Gs/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)-dependent pathway [1, 2]. In recent years, it has become increasingly clear that GPCRs play vital roles in the long-term regulation of cell proliferation and differentiation in a variety of physiologic and pathophysiologic processes [3, 4]. Accumulating evidence has proposed a new concept that GPCRs mediate the transactivation of receptor and non-receptor tyrosine kinases (RTKs) [57]. The tyrosine phosphorylation of several RTKs, including the platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), and insulin-like growth factor-1 receptor (IGFR), could be mediated by GPCRs triggered...