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.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aurora Kinase A / metabolism
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Carcinogenesis / drug effects
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin D / metabolism*
  • Cyclin-Dependent Kinases / metabolism*
  • Drug Resistance, Neoplasm / drug effects*
  • Estrogen Receptor alpha / metabolism*
  • Female
  • G1 Phase / drug effects
  • Humans
  • Membrane Proteins / metabolism*
  • Mice, Nude
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Protein Binding / drug effects
  • Protein Stability / drug effects
  • Retinoblastoma Protein / metabolism*
  • S Phase / drug effects
  • Signal Transduction
  • Survival Analysis
  • Tamoxifen / pharmacology*
  • Transcriptional Activation / drug effects
  • Treatment Outcome


  • ANKLE2 protein, human
  • Cyclin D
  • Estrogen Receptor alpha
  • Membrane Proteins
  • Nuclear Proteins
  • Retinoblastoma Protein
  • Tamoxifen
  • Aurora Kinase A
  • Cyclin-Dependent Kinases