The metabolic regulator ERRα, a downstream target of HER2/IGF-1R, as a therapeutic target in breast cancer.
The metabolic regulator ERRα, a downstream target of HER2/IGF-1R, as a therapeutic target in breast cancer.
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DOI：
10.1016/j.ccr.2011.08.023
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发表时间：
2011-10-18
期刊：
影响因子：
50.3
通讯作者：
McDonnell DP
中科院分区：
文献类型：
--
作者：
Chang CY;Kazmin D;Jasper JS;Kunder R;Zuercher WJ;McDonnell DP
A genomic signature designed to assess the activity of the estrogen-related receptor alpha (ERRα) was used to profile more than eight hundred 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-1 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 PGC1β/ERRα in the pathogenesis of breast cancers. Overexpression of ERRα has been correlated with progression of breast and ovarian cancers in several small studies. Using a genomic approach, we defined specific aspects of the activity of this receptor that track with shorter disease-free survival in multiple cohorts of breast cancer patients. Importantly, cellular models of breast cancer exhibiting high ERRα activity are more sensitive to growth inhibition by an ERRα antagonist. This finding highlights a promising treatment strategy for those aggressive tumors that currently have limited therapeutic options.
