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

Author

Listed:
  • 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
    Chinese Academy of Sciences)

  • Jin-Tang Dong

    (Nankai University
    Emory University)

  • Zhengmao Zhu

    (Nankai University)

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.

Suggested Citation

  • 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 & Zhengmao Zhu, 2018. "LEM4 confers tamoxifen resistance to breast cancer cells by activating cyclin D-CDK4/6-Rb and ERα pathway," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06309-8
    DOI: 10.1038/s41467-018-06309-8
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    Cited by:

    1. Yufan Zhou & Tian Li & Lavanya Choppavarapu & Kun Fang & Shili Lin & Victor X. Jin, 2024. "Integration of scHi-C and scRNA-seq data defines distinct 3D-regulated and biological-context dependent cell subpopulations," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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