LEM4 confers tamoxifen resistance to breast cancer cells by activating cyclin D-CDK4/6-Rb and ERα pathway. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Gao, Ang; Sun, Tonghua; Ma, Gui; Cao, Jiangran; Hu, Qingxia; Chen, Ling; Wang, Yanxin; Wang, Qianying; Sun, Jiafu; Wu, Rui; Wu, Qiao; Zhou, Jiaxi; Liu, Lin; Hu, Junjie; Dong, Jin-Tang; Zhu, Zhengmao
• Is Part Of: Nature communications. Volume 9:Issue 1(2018)
• Page Start: 1
• Page End: 17
• Publication Date: 2018-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-018-06309-8
• Languages: English
• ISSNs: 2041-1723

Abstract

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. Tamoxifen resistance is a major problem in the treatment of ERa positive breast cancer. Here, the authors show that LEM4 confers tamoxifen resistance by activating the cyclin D-CDK4/6-Rb axis and ERa signaling in endocrine-resistant breast cancer.