1. Academic Validation
  2. 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.
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.

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