Related Experiment Video

Updated: Jan 28, 2026

Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
16:24

Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells

Published on: February 21, 2014

20.7K

Neddylation Inactivation Facilitates FOXO3a Nuclear Export to Suppress Estrogen Receptor Transcription and Improve

Xiaoqing Jia1,2,3, Chunjie Li2,3, Lihui Li3

  • 1Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|March 6, 2019
PubMed
Abstract

Insights

This study reveals that higher neddylation pathway activity in breast tumors correlates with poorer prognosis and reduced estrogen receptor-alpha (ERα) expression. Inhibiting neddylation with MLN4924 suppressed ER-positive breast cancer growth, enhancing fulvestrant sensitivity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The neddylation pathway's role in breast cancer and estrogen receptor (ER) regulation is not well understood.
  • Estrogen receptor-positive (ER+) breast cancer is a major subtype, and understanding its regulation is crucial for effective treatment.

Purpose of the Study:

  • To investigate the function of the neddylation pathway in breast tumors.
  • To identify the role of neddylation in regulating ER expression.
  • To explore the mechanisms underlying neddylation's influence on ER-positive breast cancer.

Main Methods:

  • Examined expression of neddylation proteins (NAE, nedd8) in human breast tissues.
  • Assessed ER-α expression and breast cancer growth in vitro and in vivo using NAE inhibitor MLN4924.
  • Utilized 18F-FES-PET/CT, immunoblotting, chromatin immunoprecipitation, luciferase reporter assays, and CRISPR-Cas9 to elucidate regulatory mechanisms.
  • Evaluated the synergistic effect of MLN4924 and fulvestrant in an ER-positive breast cancer mouse model.

Main Results:

  • Higher NAE1 and nedd8 expression correlated with ER-positive status and poorer prognosis.
  • MLN4924 treatment significantly downregulated ER-α expression in vitro and in vivo.
  • MLN4924 affected SGK degradation, FOXO3a nuclear export, and binding to the ESR1 promoter.
  • MLN4924, alone or with fulvestrant, significantly suppressed ER-positive breast cancer growth.

Conclusions:

  • Neddylation is activated in breast tumor tissues, offering a novel target.
  • A new mechanism for ER-α regulation by neddylation was identified.
  • Neddylation inhibition presents a potential strategy to enhance fulvestrant sensitivity in ER-positive breast cancer.

More Related Videos

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay09:07

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay

Published on: December 19, 2018

6.8K
Analysis of mRNA Nuclear Export Kinetics in Mammalian Cells by Microinjection11:32

Analysis of mRNA Nuclear Export Kinetics in Mammalian Cells by Microinjection

Published on: December 4, 2010

15.8K

Related Concept Videos

Nuclear Export of mRNA02:31

Nuclear Export of mRNA

Before mRNAs are exported to the cytoplasm, it is crucial to check each mRNA for structural and functional integrity. Eukaryotic cells use several different mechanisms, collectively known as mRNA surveillance, to look for irregularities in mRNAs. Irregular or aberrant mRNA are rapidly degraded by various enzymes. If a defective mRNA escapes the surveillance, it would be translated into a protein which would either be non-functional or not function properly. One of the primary irregularities in...
8.8K
Nuclear Export of mRNA02:31

Nuclear Export of mRNA

5.4K
Nuclear Export01:42

Nuclear Export

The nucleus restricts several proteins within and allows others to pass. The restricted proteins possess a nuclear retention sequence or NRS, anchoring them to the nuclear lamins and preventing their transport to the cytosol. The non-restricted proteins, after their synthesis, are transported to their site of action, such as the cytosol or other organelles, with the help of nuclear export signals or NES.
NES are of three types- the canonical 10-residue long leucine-rich signal and other...
5.0K
Export of Mitochondrial and Chloroplast Genes02:19

Export of Mitochondrial and Chloroplast Genes

A eukaryotic cell can have up to three different types of genetic systems: nuclear, mitochondrial, and chloroplast. During evolution, organelles have exported many genes to the nucleus; this transfer is still ongoing in some plant species. Approximately 18% of the Arabidopsis thaliana nuclear genome is thought to be derived from the chloroplast’s cyanobacterial ancestor, and around 75% of the yeast genome derived from the mitochondria’s bacterial ancestor. This export has occurred...
4.2K
X-Inactivation01:58

X-Inactivation

The human X chromosome contains over ten times the number of genes as in the Y chromosome. Since males have only one X chromosome, and females have two, one might expect females to produce twice as many of the proteins, with undesirable results.
41.7K
Transducer Mechanism: Nuclear Receptors01:31

Transducer Mechanism: Nuclear Receptors

Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
2.5K