AUTHOR=Zhang Lijuan , Tian Meng , Lin Jiamao , Zhang Jianbo , Wang Haiyong , Li Zhenxiang 

TITLE=Estrogen Receptor β1 Expression Patterns Have Different Effects on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors’ Treatment Response in Epidermal Growth Factor Receptor Mutant Lung Adenocarcinoma

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.603883

DOI=10.3389/fonc.2020.603883

ISSN=2234-943X

ABSTRACT=<p>Estrogen receptor <italic>β</italic> (ER<italic>β</italic>) can regulate cellular signaling through non-genomic mechanisms, potentially promoting resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the mechanisms underlying the ER<italic>β</italic>-mediated resistance to EGFR TKIs remain poorly understood. In this study, we investigated the role of the interaction between ER<italic>β</italic>1 and ER<italic>β</italic>5 in non-genomic signaling in lung adenocarcinoma. We established PC9 cell lines stably overexpressing ER<italic>β</italic>1 or ER<italic>β</italic>1/ER<italic>β</italic>5. Immunofluorescence revealed that ER<italic>β</italic>5 overexpression partly retained ER<italic>β</italic>1 in the cytoplasm. Immunoblotting analyses revealed that EGFR pathway activation levels were higher in PC9/ER<italic>β</italic>1/5 cells than those in PC9/ER<italic>β</italic>1 or control PC9 cells. In the presence of estradiol, PI3K/AKT/mTOR pathway activation levels were higher in ER<italic>β</italic>1/5-expressing cells than those in ER<italic>β</italic>1-expressing cells. Additionally, PC9/ER<italic>β</italic>1/5 cells were less prone to the cytotoxic and pro-apoptotic effects of gefitinib compared with PC9/ER<italic>β</italic>1 or control PC9 cells. Cytoplasmic ER<italic>β</italic>1 was associated with poor progression-free survival in lung cancer patients treated with EGFR TKIs. These results suggest that cytoplasmic ER<italic>β</italic>1 was responsible for EGFR TKI resistance slightly through non-genomic mechanism in EGFR mutant lung adenocarcinoma.</p>