title: β2-AR signaling controls trastuzumab resistance-dependent pathway.
abstract: Currently, trastuzumab resistance is a major clinical problem in the treatment of Her2-overexpressing breast cancer. The underlying molecular mechanisms are not fully understood. Our previous study demonstrates that β2-adrenergic receptor (β2-AR) and Her2 comprise a positive feedback loop in human breast cancer cells and that crosstalk between Her2 and β2-AR affects the bio-behaviors of breast cancer cells, suggesting that the β2-AR activation may be involved in trastuzumab resistance. In this study, we show that the expression of β2-AR, which mediates most catecholamine-induced effects, negatively correlates with trastuzumab response in the patients with Her2-overexpressing breast cancer. Catecholamines potently antagonize the anti-proliferative effects of trastuzumab both in vitro and in vivo. Catecholamine stimulation upregulates the expression of miR-21 and MUC-1 by activating Her2 and STAT3, leading to deficiency of phosphatase and tensin homolog and activation of phosphatidylinositol-3-kinase (PI3K) and Akt. Through inhibition of miR-199a/b-3p, catecholamines induce the mammalian target of rapamycin (mTOR) activation. Thus, trastuzumab resistance-dependent PI3K/Akt/mTOR pathway is controlled by catecholamine-induced β2-AR activation. The data indicate that β2-AR is a reliable molecular marker for prediction of response probability to trastuzumab-based therapy in breast cancer. We also demonstrate that β-blocker propranolol not only enhances the antitumor activities of trastuzumab but also re-sensitizes the resistant cells to trastuzumab. Our retrospective study shows that concurrent treatment of β-blocker and trastuzumab significantly improved progression-free survival and overall survival in the patients with Her2-overexpressing metastatic breast cancer, implicating the possibility for combination therapy with trastuzumab plus β-blocker in Her2-overexpressing breast cancer.
authors: Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing, China.
authors: D
authors: D
authors: Liu
authors: Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing, China.
authors: Z
authors: Z
authors: Yang
authors: Department of Oncology, 307 Hospital of People's Liberation Army, Beijing, China.
authors: T
authors: T
authors: Wang
authors: Yangtze River Pharmaceutical Group, Beijing Haiyan Pharmaceutical Co. Ltd, Beijing, China.
authors: Z
authors: Z
authors: Yang
authors: Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing, China.
authors: H
authors: H
authors: Chen
authors: Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing, China.
authors: Y
authors: Y
authors: Hu
authors: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
authors: C
authors: C
authors: Hu
authors: Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing, China.
authors: L
authors: L
authors: Guo
authors: Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing, China.
authors: Q
authors: Q
authors: Deng
authors: Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing, China.
authors: Y
authors: Y
authors: Liu
authors: Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing, China.
authors: M
authors: M
authors: Yu
authors: Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing, China.
authors: M
authors: M
authors: Shi
authors: Department of Oncology, The First Affiliated Hospital, General Hospital of People's Liberation Army, Beijing, China.
authors: N
authors: N
authors: Du
authors: Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing, China.
authors: N
authors: N
authors: Guo
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction; D043823:Taxoids / Q000008:administration & dosage; D000068878:Trastuzumab / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D003520:Cyclophosphamide; D000077143:Docetaxel; D015251:Epirubicin; D018719:Erb-b2 Receptor Tyrosine Kinases; D018343:Receptors, Adrenergic, beta-2; D043823:Taxoids; D000068878:Trastuzumab; C508053:ERBB2 protein, human