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

Abstract

A genomic signature designed to assess the activity of the estrogen-related receptor alpha (ERRα) was used to profile more than 800 breast tumors, revealing a shorter disease-free survival in patients with tumors exhibiting elevated receptor activity. Importantly, this signature also predicted the ability of an ERRα antagonist, XCT790, to inhibit proliferation in cellular models of breast cancer. Using a chemical genomic approach, it was determined that activation of the Her2/IGF-1R signaling pathways and subsequent C-MYC stabilization upregulate the expression of peroxisome proliferator-activated receptor gamma coactivator-1 beta (PGC-1β), an obligate cofactor for ERRα activity. PGC-1β knockdown in breast cancer cells impaired ERRα signaling and reduced cell proliferation, implicating a functional role for PGC-1β/ERRα in the pathogenesis of breast cancers.

• Authors: Ching-yi Chang, Dmitri Kazmin, Jeff S Jasper, Rebecca Kunder, William J Zuercher, Donald P McDonnell
• Journal: Cancer cell (Cancer Cell) Vol. 20 Issue 4 Pg. 500-10 (Oct 18 2011) ISSN: 1878-3686 [Electronic] United States
• PMID: 22014575 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Carrier Proteins
• ERRalpha estrogen-related receptor
• Nitriles
• PPARGC1B protein, human
• RNA-Binding Proteins
• Receptors, Estrogen
• Thiazoles
• XCT790
• Receptor, ErbB-2
• Receptor, IGF Type 1

Topics

• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Carrier Proteins (genetics)
• Cell Proliferation (drug effects)
• Female
• Humans
• Nitriles (pharmacology)
• RNA-Binding Proteins
• Receptor, ErbB-2 (metabolism)
• Receptor, IGF Type 1 (metabolism)
• Receptors, Estrogen (antagonists & inhibitors, genetics, metabolism, physiology)
• Signal Transduction
• Thiazoles (pharmacology)