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The metabolic regulator ERR?, 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 (ERR?) 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 ERR? 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-1?), an obligate cofactor for ERR? activity. PGC-1? knockdown in breast cancer cells impaired ERR? signaling and reduced cell proliferation, implicating a functional role for PGC-1?/ERR? in the pathogenesis of breast cancers.

SUBMITTER: Chang CY

PROVIDER: S-EPMC3199323 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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

Chang Ching-yi CY Kazmin Dmitri D Jasper Jeff S JS Kunder Rebecca R Zuercher William J WJ McDonnell Donald P DP

Cancer cell 20111001 4

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 pa ...[more]

PMID: 22014575

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Project description:The type I insulin-like growth factor-1 receptor is a well-described target in breast cancer and multiple clinical trials examining insulin-like growth factor-1 receptor have been completed. Unfortunately, monoclonal antibodies and tyrosine kinase inhibitors targeting insulin-like growth factor-1 receptor failed in phase III breast clinical trials for several reasons. First, insulin-like growth factor-1 receptor antibody therapy resulted in hyperglycemia and metabolic syndrome most likely due to disruption of insulin-like growth factor-1 homeostasis and subsequent growth hormone elevation. Growth hormone elevation induces insulin resistance, hence a subsequent elevation of insulin and the potential for activation of insulin receptor. Second, the insulin-like growth factor-1 receptor and insulin receptor are highly homologous in amino acid sequence, structure, and function. These two receptors bind insulin, insulin-like growth factor-1 and insulin-like growth factor-2, to regulate glucose uptake and other cellular functions. Hybrid receptors composed of one chain of insulin-like growth factor-1 receptor and insulin receptor also participate in signaling. Third, since all the monoclonal antibodies were specific for insulin-like growth factor-1 receptor, any pathophysiologic role for insulin receptor was not inhibited. While the insulin-like growth factor-1 receptor tyrosine kinase inhibitors effectively inhibited both insulin-like growth factor-1 receptor and insulin receptor, these drugs are not being further developed likely due to their metabolic toxicities. Insulin-like growth factor-1/2 neutralizing antibodies are still being studied in early phase clinical trials. Perhaps a more comprehensive strategy of targeting the insulin-like growth factor-1 receptor network would be successful. For example, targeting receptor, ligand and downstream signaling molecules such as phosphatidylinositol 3'-kinase or particularly the insulin receptor substrate adapter proteins might result in a complete blockade of insulin-like growth factor-1 receptor/insulin receptor biological functions.

Dataset Information

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

Publications

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

Similar Datasets

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