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

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

  • Nat Commun. 2018 Oct 9;9(1):4180. doi: 10.1038/s41467-018-06309-8.
Ang Gao 1,  Tonghua Sun 1,  Gui Ma 1,  Jiangran Cao 1,  Qingxia Hu 1,  Ling Chen 2,  Yanxin Wang 3,  Qianying Wang 1,  Jiafu Sun 1,  Rui Wu 1,  Qiao Wu 1,  Jiaxi Zhou 4,  Lin Liu 1,  Junjie Hu 5 6,  Jin-Tang Dong 7 8,  Zhengmao Zhu 9
Affiliations

Affiliations

  • 1 Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China.
  • 2 Department of Pathology, Tianjin Central Hospital of Gynecology and Obstetrics, Tianjin, 300100, China.
  • 3 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 4 State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China.
  • 5 Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China. huj@ibp.ac.cn.
  • 6 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. huj@ibp.ac.cn.
  • 7 Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China. j.dong@emory.edu.
  • 8 Department of Hematology and Medical Oncology, School of Medicine, Winship Cancer Institute, Emory University, Atlanta, Georgia. j.dong@emory.edu.
  • 9 Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China. zhuzhengmao@nankai.edu.cn.
PMID: 30301939 DOI: 10.1038/s41467-018-06309-8
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-50767
    99.94%, CDK4/6 Inhibitor
    CDK