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Article

Estrogen receptor β1 activation accelerates resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in non-small cell lung cancer

  • Authors:
    • Shengling Fu
    • Changyu Liu
    • Quanfu Huang
    • Sheng Fan
    • Hexiao Tang
    • Xiangning Fu
    • Bo Ai
    • Yongde Liao
    • Qian Chu
  • View Affiliations / Copyright

    Affiliations: Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
  • Pages: 1313-1321
    |
    Published online on: January 4, 2018
       https://doi.org/10.3892/or.2018.6186
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Abstract

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths worldwide. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR‑TKIs) have revolutionized the treatment of patients with advanced EGFR-mutant NSCLC. However, drug resistance eventually develops in the majority of patients despite an excellent initial response. The present study aimed to investigate the mechanism of acquired resistance to EGFR-TKIs and to explore strategies to overcome the resistance to EGFR-TKIs from a gender perspective. PC9 and Hcc827 cell lines, sensitized to EGFR-TKI, and secondary TKI-resistant PC9-ER (erlotinib resistant) and Hcc827-ER cell lines were evaluated for the expression of ERβ1. The proliferative ability of both cell lines was analyzed after transfection of siRNA-ERβ1 using Cell Counting Kit-8 and colony formation assays. Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and Akt activation were detected. The co-inhibition efficiency of erlotinib and fulvestrant was analyzed in PC9-ER xenografts. The expression of ERβ1 was investigated in tumor tissues of EGFR-TKI-treated patients, and its correlation with clinicopathological factors and progression-free survival (PFS) was assessed. The expression of ERβ1 was upregulated secondary to EGFR-TKIs in PC9 and Hcc827 cell lines, with β-estradiol dependence. Both PC9-ER and Hcc827-ER cell lines were re-sensitized to erlotinib after downregulation of the expression of ERβ1. ERK1/2 and Akt pathways were activated following the silencing of the expression of ERβ1 in PC9-ER and Hcc827 cell lines. The co-treatment of erlotinib and fulvestrant exhibited better growth inhibitory efficiency compared with the treatment of each agent alone in PC9-ER-derived xenografts. Primary NSCLC samples of 53 patients treated with EGFR-TKIs were analyzed. ERβ1 was highly expressed, and the strong expression of cytoplasmic ERβ1 was related to a shorter PFS. In conclusion, ERβ1 was activated in EGFR-TKI secondary resistance. The downregulation of ERβ1 sensitized the cells to EGFR-TKIs. ERβ1 may be a key molecule in EGFR-TKI therapy. In addition, anti-ERβ1 treatment may reverse TKI resistance.
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Copy and paste a formatted citation
Spandidos Publications style
Fu S, Liu C, Huang Q, Fan S, Tang H, Fu X, Ai B, Liao Y and Chu Q: Estrogen receptor β1 activation accelerates resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in non-small cell lung cancer. Oncol Rep 39: 1313-1321, 2018.
APA
Fu, S., Liu, C., Huang, Q., Fan, S., Tang, H., Fu, X. ... Chu, Q. (2018). Estrogen receptor β1 activation accelerates resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in non-small cell lung cancer. Oncology Reports, 39, 1313-1321. https://doi.org/10.3892/or.2018.6186
MLA
Fu, S., Liu, C., Huang, Q., Fan, S., Tang, H., Fu, X., Ai, B., Liao, Y., Chu, Q."Estrogen receptor β1 activation accelerates resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in non-small cell lung cancer". Oncology Reports 39.3 (2018): 1313-1321.
Chicago
Fu, S., Liu, C., Huang, Q., Fan, S., Tang, H., Fu, X., Ai, B., Liao, Y., Chu, Q."Estrogen receptor β1 activation accelerates resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in non-small cell lung cancer". Oncology Reports 39, no. 3 (2018): 1313-1321. https://doi.org/10.3892/or.2018.6186
Copy and paste a formatted citation
x
Spandidos Publications style
Fu S, Liu C, Huang Q, Fan S, Tang H, Fu X, Ai B, Liao Y and Chu Q: Estrogen receptor β1 activation accelerates resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in non-small cell lung cancer. Oncol Rep 39: 1313-1321, 2018.
APA
Fu, S., Liu, C., Huang, Q., Fan, S., Tang, H., Fu, X. ... Chu, Q. (2018). Estrogen receptor β1 activation accelerates resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in non-small cell lung cancer. Oncology Reports, 39, 1313-1321. https://doi.org/10.3892/or.2018.6186
MLA
Fu, S., Liu, C., Huang, Q., Fan, S., Tang, H., Fu, X., Ai, B., Liao, Y., Chu, Q."Estrogen receptor β1 activation accelerates resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in non-small cell lung cancer". Oncology Reports 39.3 (2018): 1313-1321.
Chicago
Fu, S., Liu, C., Huang, Q., Fan, S., Tang, H., Fu, X., Ai, B., Liao, Y., Chu, Q."Estrogen receptor β1 activation accelerates resistance to epidermal growth factor receptor-tyrosine kinase inhibitors in non-small cell lung cancer". Oncology Reports 39, no. 3 (2018): 1313-1321. https://doi.org/10.3892/or.2018.6186
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