The β2-adrenergic receptor and Her2 comprise a positive feedback loop in human breast cancer cells.
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.
Shi
Ming
M
Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, People's Republic of China.
Liu
Dan
D
Duan
Huijun
H
Qian
Lu
L
Wang
Lina
L
Niu
Lijia
L
Zhang
Huipeng
H
Yong
Zheng
Z
Gong
Zehui
Z
Song
Lun
L
Yu
Ming
M
Hu
Meiru
M
Xia
Qing
Q
Shen
Beifen
B
Guo
Ning
N
D001483:Base Sequence; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002395:Catecholamines / Q000096:biosynthesis; D045744:Cell Line, Tumor; D004837:Epinephrine / Q000096:biosynthesis / Q000737:chemistry; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D009154:Mutation; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics* / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
D002395:Catecholamines; D004837:Epinephrine; D048049:Extracellular Signal-Regulated MAP Kinases; D007545:Isoproterenol; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D018343:Receptors, Adrenergic, beta-2; D050796:STAT3 Transcription Factor