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G protein-coupled estrogen receptor (GPER) mediates NSCLC progression induced by 17β-estradiol (E2) and selective agonist G1

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Abstract

Estrogen classically drives lung cancer development via estrogen receptor β (ERβ). However, fulvestrant, an anti-estrogen-based endocrine therapeutic treatment, shows limited effects for non-small cell lung cancer (NSCLC) in phase II clinical trials. G protein-coupled estrogen receptor (GPER), a third estrogen receptor that binds to estrogen, has been found to be activated by fulvestrant, stimulating the progression of breast, endometrial, and ovarian cancers. We here demonstrated that cytoplasm-GPER (cGPER) (80.49 %) and nucleus-GPER (53.05 %) were detected by immunohistochemical analysis in NSCLC samples. cGPER expression was related to stages IIIA–IV, lymph node metastasis, and poorly differentiated NSCLC. Selective agonist G1 and 17β-estradiol (E2) promoted the GPER-mediated proliferation, invasion, and migration of NSCLC cells. Additionally, in vitro administration of E2 and G1 increased the number of tumor nodules, tumor grade, and tumor index in a urethane-induced adenocarcinoma model. Importantly, the pro-tumorigenic effects of GPER induced by E2 were significantly reduced by co-administering the GPER inhibitor G15 and the ERβ inhibitor fulvestrant, as compared to administering fulvestrant alone both in vitro and in vivo. Moreover, the phosphorylation of MAPK and Akt was involved in E2/G1-induced GPER activation. In conclusion, our results indicated that a pro-tumor function of GPER exists that mediated E2-/G1-dependent NSCLC progression and showed better efficiency regarding the co-targeting of GPER and ERβ, providing a rationale for further investigation of anti-estrogen clinical therapy.

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Acknowledgments

The authors thank Ensong Guo, **ao Wei, Hao Lu and Changlin Zhang from Key Laboratory of Cancer Invasion and Metastasis (Huazhong University of Science and Technology), Ministry of Education, for their kind help. This study was funded by National Natural Science Foundation of China (NSFC), Grant Number: 81272590, 81402163, and Wuhan Municipal Human Resources and Social Security Bureau, Grant Number: 2011415.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Authors and Affiliations

  1. Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Dadao Street 1095, Wuhan, 430030, Hubei Province, China

    Changyu Liu, Yongde Liao, Sheng Fan & Zhixiao Jiang

  2. Department of Intensive Care Unit, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China

    Hexiao Tang

  3. Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Huazhong University of Science and Technology, Wuhan, China

    Bo Zhou

  4. Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China

    **g **ong & Sheng Zhou

  5. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China

    Man Zou

  6. Department of Respiratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China

    Jianmiao Wang

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  1. Changyu Liu
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Correspondence to Yongde Liao.

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Liu, C., Liao, Y., Fan, S. et al. G protein-coupled estrogen receptor (GPER) mediates NSCLC progression induced by 17β-estradiol (E2) and selective agonist G1. Med Oncol 32, 104 (2015). https://doi.org/10.1007/s12032-015-0558-2

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  • DOI: https://doi.org/10.1007/s12032-015-0558-2

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