ERα36 as a Potential Therapeutic Target for Tamoxifen-Resistant Breast Cancer Cell Line Through EGFR/ERK Signaling Pathway
Authors Li G, Zhang J, Xu Z, Li Z
Received 7 August 2019
Accepted for publication 16 December 2019
Published 14 January 2020 Volume 2020:12 Pages 265—275
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 2
Editor who approved publication: Professor Harikrishna Nakshatri
Guangliang Li, 1 Jing Zhang, 2 Zhenzhen Xu, 2 Zhongqi Li 2
1Institute of Cancer Research and Basic Medicine (ICBM), Chinese Academy of Sciences, Department of Medical Oncology (Breast), Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, People’s Republic of China; 2Department of Surgical Oncology, The 1st Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, People’s Republic of China
Correspondence: Guangliang Li
Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Department of Medical Oncology (Breast), Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, No. 1, Banshan East Road, Hangzhou, Zhejiang 310022, People’s Republic of China
Department of Surgical Oncology, The 1st Affiliated Hospital, School of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou 310003, People’s Republic of China
Background: Acquired tamoxifen resistance is one of the major barriers to the successful treatment of breast cancer. Recently, overexpression of ERα 36 was demonstrated to be a potential mechanism for the generation of acquired tamoxifen resistance. This study aims to evaluate the possibility of ERα 36 being a therapeutic target for tamoxifen-resistant breast cancer.
Methods: A tamoxifen-resistant cell subline (MCF-7/TAM) was established by culturing MCF-7 cells in medium plus 1 μM tamoxifen over 6 months. Colony-forming assay was used to determine the sensitivity of MCF-7/TAM cells to tamoxifen. Stable transfection was used to knockdown ERα 36 expression in MCF-7/TAM cells. MTT assay and Transwell migration assay were used to assess the in vitro proliferation and migration, respectively. Nude mouse tumorigenicity assay was used to evaluate in vivo tumorigenicity. Western blot analysis and quantitative real-time PCR (qRT-PCR) were used to examine the expression of ERα 36, ERα, EGFR and phosphorylated ERK1/2. The dual-luciferase reporter assay was used to determine the effect of ERα 36 on the activity of EGFR-promotor.
Results: MCF-7/TAM cells possessed greatly increased ERα 36 expression and EGFR expression and exhibited significantly increased in vitro proliferation and migration ability, as well as increased in vivo tumor growth ability, compared to parental MCF-7 cells. Knockdown of ERα 36 expression inhibited in vitro proliferation and migration, as well as in vivo tumor growth ability of MCF-7/TAM cells. ERα 36 regulated EGFR expression at the transcriptional level, and knockdown of ERα 36 in MCF-7/TAM cells downregulated EGFR expression and then blocked EGFR/ERK signaling pathway.
Conclusion: Knockdown of ERα 36 inhibits the growth of MCF-7/TAM cells in vitro and in vivo by blocking EGFR/ERK signaling pathway. ERα 36 may be a candidate therapeutic target for the treatment of tamoxifen-resistant breast cancer.
Keywords: breast cancer, acquired tamoxifen resistance, ERα 36, EGFR/ERK signaling
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