title: ERβ localization influenced outcomes of EGFR-TKI treatment in NSCLC patients with EGFR mutations.
abstract: 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.
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital &Beijing Institute for Cancer Research, Beijing, China.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital &Beijing Institute for Cancer Research, Beijing, China.
authors.forename: Zhenxiang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Oncology, Aviation General Hospital, Beijing, China.
authors.forename: Xiaosheng
authors.initials: X
authors.lastname: Ding
authors.affiliation: Metabolomics Center, National Institute of Biological Sciences, Beijing, China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital &Beijing Institute for Cancer Research, Beijing, China.
authors.forename: Zhentao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital &Beijing Institute for Cancer Research, Beijing, China.
authors.forename: Tongtong
authors.initials: T
authors.lastname: An
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital &Beijing Institute for Cancer Research, Beijing, China.
authors.forename: Jianchun
authors.initials: J
authors.lastname: Duan
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital &Beijing Institute for Cancer Research, Beijing, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital &Beijing Institute for Cancer Research, Beijing, China.
authors.forename: Meina
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital &Beijing Institute for Cancer Research, Beijing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital &Beijing Institute for Cancer Research, Beijing, China.
authors.forename: Minglei
authors.initials: M
authors.lastname: Zhuo
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital &Beijing Institute for Cancer Research, Beijing, China.
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital &Beijing Institute for Cancer Research, Beijing, China.
authors.forename: Shuhang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital &Beijing Institute for Cancer Research, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital &Beijing Institute for Cancer Research, Beijing, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Bai
authors.affiliation: Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital &Beijing Institute for Cancer Research, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
mesh_terms: D016475:3T3 Cells; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D044466:Asian People; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D045744:Cell Line, Tumor; D002681:China; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D004958:Estradiol / Q000031:analogs & derivatives / Q000627:therapeutic use; D065171:Estrogen Receptor Antagonists / Q000627:therapeutic use; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005260:Female; D000077267:Fulvestrant; D000077156:Gefitinib; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D065171:Estrogen Receptor Antagonists; D047629:Estrogen Receptor beta; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077267:Fulvestrant; D004958:Estradiol; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib