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Updated: Jul 14, 2026
10:36
Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
The estrogen receptor alpha:insulin receptor substrate 1 complex in breast cancer: structure-function relationships
1Dipartimento Farmaco Biologico, University of Calabria, Arcavacata di Rende, Cosenza. dsisci@unical.it
Summary
Insulin receptor substrate 1 (IRS-1) directly binds estrogen receptor alpha (ERalpha) and influences its activity. IRS-1 acts as a repressor for liganded ERalpha but a coactivator for unliganded ERalpha in breast cancer cells.
Area of Science:
- Molecular Biology
- Cell Biology
- Endocrinology
Background:
- Insulin receptor substrate 1 (IRS-1) is crucial for crosstalk between estrogen receptor alpha (ERalpha) and insulin-like growth factor 1 (IGF-1) in breast cancer.
- IRS-1 binds ERalpha, translocates to the nucleus, and modulates ERalpha-dependent transcription at estrogen response elements (ERE).
Purpose of the Study:
- To investigate the structure-function relationships of the ERalpha:IRS-1 complex.
- To analyze ERalpha/IRS-1 interactions under IGF-1 and/or estradiol (E2) stimulation.
Main Methods:
- Utilized ERalpha and IRS-1 deletion mutants to study interactions.
- Employed chromatin immunoprecipitation and gene reporter assays to examine IRS-1 binding and transcriptional roles.
- Used RNA interference (RNAi) to assess IRS-1's requirement in ERalpha function.
Main Results:
- Nuclear translocation of IRS-1 was induced by E2, IGF-1, or both.
- Direct binding between ERalpha and IRS-1 involves ERalpha's AF-1/DNA binding domain (DBD) and two IRS-1 regions (N-terminal PH domain and C-terminal region).
- IRS-1 knockdown abrogated IGF-1-dependent activity of unliganded ERalpha but enhanced the activity of liganded ERalpha.
Conclusions:
- ERalpha/IRS-1 interactions are direct, involving specific domains on both proteins.
- IRS-1 functions as a repressor for liganded ERalpha and a coactivator for unliganded ERalpha.
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