LEM4 confers tamoxifen resistance to breast cancer cells by activating cyclin D-CDK4/6-Rb and ERα pathway

• Type of Material: Article
• Authors: Ang Gao, Nankai University; Tonghua Sun, Nankai University; Gui Ma, Nankai University; Jiangran Cao, Nankai University; Qingxia Hu, Nankai University; Ling Chen, Tianjin Central Hospital of Obstetrics and Gynecology; Yanxin Wang, Yong Loo Lin School of Medicine; Qianying Wang, Nankai University; Jiafu Sun, Nankai University; Rui Wu, Nankai University; Qiao Wu, Nankai University; Jiaxi Zhou, Institute of Hematology and Blood Disease Hospital; Lin Liu, Nankai University; Junjie Hu, Nankai University; Jin-Tang Dong, Emory University; Zhengmao Zhu, Nankai University
• Language: English
• Date: 2018-12-01
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2018, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-018-06309-8
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 9
• Issue: 1
• Start Page: 4180
• End Page: 4180
• Grant/Funding Information: The study was supported by the National Natural Science Foundation of China (Grant No. 91649107 and 81402320), the Natural Science Foundation of Tianjin City of China (Grant No. 17JCYBJC24100 and 16JCYBJC27000), and the Strategic Priority Research Program (Pilot study) “Biological basis of aging and therapeutic strategies” of the Chinese Academy of Sciences (grant XDPB10).
• Keywords: oncogenes; cell-cycle exit; breast cancer
• Research Categories: Health Sciences, Oncology

Abstract

The elucidation of molecular events that confer tamoxifen resistance to estrogen receptor α (ER) positive breast cancer is of major scientific and therapeutic importance. Here, we report that LEM4 overexpression renders ER+ breast cancer cells resistant to tamoxifen by activating the cyclin D-CDK4/6 axis and the ERα signaling. We show that LEM4 overexpression accelerates tumor growth. Interaction with LEM4 stabilizes CDK4 and Rb, promotes Rb phosphorylation and the G1/S phase transition. LEM4 depletion or combined tamoxifen and PD0332991 treatment significantly reverses tamoxifen resistance. Furthermore, LEM4 interacts with and stabilizes both Aurora-A and ERα, promotes Aurora-A mediated phosphorylation of ERα-Ser167, leading to increase in ERα DNA-binding and transactivation activity. Elevated levels of LEM4 correlates with poorer relapse-free survival in patients with ER+ breast cancer undergoing endocrine therapy. Thus, LEM4 represents a prognostic marker and an attractive target for breast cancer therapeutics. Functional antagonism of LEM4 could overcome tamoxifen resistance.