ERβ localization influenced outcomes of EGFR-TKI treatment in NSCLC patients with EGFR mutations

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作者
Zhijie Wang
Zhenxiang Li
Xiaosheng Ding
Zhirong Shen
Zhentao Liu
Tongtong An
Jianchun Duan
Jia Zhong
Meina Wu
Jun Zhao
Minglei Zhuo
Yuyan Wang
Shuhang Wang
Yu Sun
Hua Bai
Jie Wang
机构
[1] Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education),Department of Thoracic Medical Oncology
[2] Beijing Cancer Hospital & Beijing Institute for Cancer Research,Department of Oncology
[3] Aviation General Hospital,Department of Pathology
[4] Metabolomics Center,undefined
[5] National Institute of Biological Sciences,undefined
[6] Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education),undefined
[7] Beijing Cancer Hospital & Beijing Institute for Cancer Research,undefined
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Effects of estrogen receptorβ (ERβ) localization on epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC) are unknown. First, we analyzed the relationship between ERβ localization determined by immunohistochemistry and EGFR-TKI outcomes in 184 patients with advanced NSCLC and found that ERβ expression localized in the cytoplasm and/or nucleus. The frequency of cytoplasmic ERβ (c-ERβ) and nuclear ERβ (n-ERβ) co-expression was 12% (22/184). C-ERβ and n-ERβ co-expression was correlated with poor median progression-free survival compared to patients without co-expression. In subsequent in vitro experiments, PC9 cells transfected with ERβ isoform1 (ERβ1, strong expression of both c-ERβ and n-ERβ) were more resistant to gefitinib than PC9 cells transfected with ERβ isoform2 or 5 (ERβ2 or ERβ5, strong expression of ERβ in cytoplasm but not nucleus). Resistance was identified due to interactions between ERβ1 and other isoforms and mediated by activation of non-genomic pathways. Moreover, gefitinib resistance was reversed by a combination treatment with gefitinib and fulvestrant, both in cell lines and in one NSCLC patient. These results suggested that c-ERβ and n-ERβ co-expression was a potential molecular indicator of EGFR-TKI resistance, which might be overcome by combining EGFR-TKI and ER antagonist.
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