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
  • 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. [email protected].
  • 6. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. [email protected].
  • 7. Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China. [email protected].
  • 8. Department of Hematology and Medical Oncology, School of Medicine, Winship Cancer Institute, Emory University, Atlanta, Georgia. [email protected].
  • 9. Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China. [email protected].
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.

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