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Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
10:36

Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer

Published on: March 17, 2016

An integrated bioinformatics approach identifies elevated cyclin E2 expression and E2F activity as distinct features

Lei Huang1, Shuangping Zhao, Jonna M Frasor

  • 1Department of Bioengineering, University of Illinois at Chicago, Illinois, United States of America.

Plos One
|July 27, 2011
PubMed

Insights

Half of estrogen receptor-positive breast cancers resist endocrine therapy. This study identified cell cycle and proliferation genes in resistant tumors, revealing phenothiazines as a potential treatment to overcome tamoxifen resistance.

Area of Science:

  • Oncology
  • Bioinformatics
  • Genomics

Background:

  • Estrogen receptor (ER)-positive breast tumors often develop resistance to endocrine therapy, necessitating new treatment strategies.
  • Understanding the molecular mechanisms of tamoxifen resistance is crucial for improving patient outcomes.

Purpose of the Study:

  • To identify molecular mechanisms driving tamoxifen resistance in ER-positive breast cancer using an integrative bioinformatics approach.
  • To uncover potential therapeutic strategies to overcome endocrine therapy resistance.

Main Methods:

  • Analysis of three gene expression profiling datasets from tamoxifen-resistant versus sensitive breast tumors.
  • Gene function and enrichment analysis, intrinsic subtype correlation, and Connectivity Map analysis.
  • In vitro validation of identified small molecules in tamoxifen-resistant cell lines.

Main Results:

  • Despite limited overlap in differentially expressed genes, functional similarity was observed across datasets.
  • Tamoxifen-resistant tumors showed enriched expression of cell cycle/proliferation genes and elevated E2F transcription factor activity, correlating with the Luminal subtype.
  • Phenothiazines were identified as small molecules that reverse the resistant gene signature and inhibit proliferation in resistant cells.

Conclusions:

  • An integrated bioinformatics approach can identify key pathways and therapeutic targets for tamoxifen-resistant breast cancer.
  • Phenothiazines show promise as a therapeutic option to overcome endocrine therapy resistance in ER-positive breast cancer.

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