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β2-AR signaling controls trastuzumab resistance-dependent pathway

Oncogene volume 35, pages 47–58 (2016)Cite this article

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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.

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Acknowledgements

This work is supported by National Basic Research Program of China (973 program, no. 2010CB911904), National Key Technologies R&D Program for New Drugs (2013ZX09102056), the National High-Tech Research and Development Plan (863 program, no. 2014AA020604), National Natural Science Foundation of China (no. 31370825, 81402562 and 81272232) and Beijing Natural Science Foundation (no. 7122124 and 7132163).

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  1. D Liu, Z Yang and T Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathophysiology, Institute of Basic Medical Sciences, Beijing, China

    D Liu, Z Yang, H Chen, Y Hu, L Guo, Q Deng, Y Liu, M Yu, M Shi & N Guo

  2. Department of Oncology, 307 Hospital of People's Liberation Army, Beijing, China

    T Wang

  3. Yangtze River Pharmaceutical Group, Beijing Haiyan Pharmaceutical Co. Ltd,, Beijing, China

    Z Yang

  4. State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China

    C Hu

  5. Department of Oncology, The First Affiliated Hospital, General Hospital of People's Liberation Army, Beijing, China

    N Du

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Liu, D., Yang, Z., Wang, T. et al. β2-AR signaling controls trastuzumab resistance-dependent pathway. Oncogene 35, 47–58 (2016). https://doi.org/10.1038/onc.2015.58

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