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Author Notes:

Correspondence and requests for materials should be addressed to J.H. (email: huj@ibp.ac.cn) or to J.-T.D. (email: j.dong@emory.edu) or to Z.Z. (email: zhuzhengmao@nankai.edu.cn)

Z.Z., J.T.D., and J.H. conceived and designed the study.

A.G., T.S., and G.M. performed cell culture experiments, histology, immunohistochemistry, and analysis.

A.G. and J.C. performed Mouse xenograft studies.

Z.Z. and L.C. contributed tissue array experiments and recording data analysis.

Z.Z. and Y.W. performed Kaplan–Meier analysis.

A.G. and Q.W. performed cell cycle analysis.

Q.H., T.S., Q.W., and J.S. contributed the GST-pulldown and IP and results.

A.G. and R.W. contributed CHX chase assay and results.

J.Z., L.L., J.T.D. provided comments on the manuscript.

Z.Z., J.H., and A.G. contributed manuscript preparation.

The authors thank Drs. Yushan Zhu and Jun Zhou for providing plasmids and materials.

The authors thank Dr Tao Zhu for providing MCF7-TAMR cell model.

The authors declare no competing interests.

Subject:

Research Funding:

The study was supported by the National Natural Science Foundation of China (Grant No. 91649107 and 81402320), the Natural Science Foundation of Tianjin City of China (Grant No. 17JCYBJC24100 and 16JCYBJC27000), and the Strategic Priority Research Program (Pilot study) “Biological basis of aging and therapeutic strategies” of the Chinese Academy of Sciences (grant XDPB10).

Keywords:

  • breast cancer
  • cell-cycle exit
  • oncogenes

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

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Journal Title:

Nature Communications

Volume:

Volume 9, Number 1

Publisher:

, Pages 4180-4180

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2018, The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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