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

Ang Gao, Tonghua Sun, Gui Ma, Jiangran Cao, Qingxia Hu, Ling Chen, Yanxin Wang, Qianying Wang, Jiafu Sun, Rui Wu, Qiao Wu, Jiaxi Zhou, Lin Liu, Junjie Hu (), Jin-Tang Dong () and Zhengmao Zhu ()
Additional contact information
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 Gynecology and Obstetrics
Yanxin Wang: National University of Singapore
Qianying Wang: Nankai University
Jiafu Sun: Nankai University
Rui Wu: Nankai University
Qiao Wu: Nankai University
Jiaxi Zhou: Chinese Academy of Medical Sciences & Peking Union Medical College
Lin Liu: Nankai University
Junjie Hu: Nankai University
Jin-Tang Dong: Nankai University
Zhengmao Zhu: Nankai University

Nature Communications, 2018, vol. 9, issue 1, 1-17

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.

Date: 2018
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-018-06309-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06309-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-018-06309-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().