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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

The metabolic regulator ERRα, a downstream target of HER2/IGF-1R, as a therapeutic target in breast cancer

Ching-yi Chang1, Dmitri Kazmin, Jeff S Jasper

  • 1Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.

Cancer Cell
|October 22, 2011
PubMed

Insights

Elevated estrogen-related receptor alpha (ERRα) activity in breast tumors correlates with shorter disease-free survival. Targeting ERRα with antagonists like XCT790 may inhibit cancer cell proliferation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • Estrogen-related receptor alpha (ERRα) is implicated in various cancers.
  • Understanding ERRα activity is crucial for developing targeted breast cancer therapies.

Purpose of the Study:

  • To develop and validate a genomic signature for assessing ERRα activity in breast tumors.
  • To investigate the role of ERRα and its cofactors in breast cancer pathogenesis and treatment response.

Main Methods:

  • Genomic profiling of over 800 breast tumors using an ERRα activity signature.
  • Testing the efficacy of an ERRα antagonist (XCT790) in cellular breast cancer models.
  • Employing a chemical genomic approach to identify signaling pathways regulating ERRα activity.

Main Results:

  • Elevated ERRα activity in tumors was associated with shorter disease-free survival.
  • The genomic signature predicted sensitivity to the ERRα antagonist XCT790.
  • Her2/IGF-1R signaling and C-MYC stabilization were found to upregulate peroxisome proliferator-activated receptor gamma coactivator-1 beta (PGC-1β), a key cofactor for ERRα.
  • PGC-1β knockdown inhibited ERRα signaling and reduced breast cancer cell proliferation.

Conclusions:

  • A validated genomic signature can assess ERRα activity and predict patient outcomes in breast cancer.
  • The PGC-1β/ERRα pathway is a critical driver of breast cancer proliferation and a potential therapeutic target.

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