The Metabolic Regulator ERRα, a Downstream Target of HER2/IGF-1R, as a Therapeutic Target in Breast Cancer

A genomic signature designed to assess the activity of the estrogen-related receptor alpha (ERR alpha) 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 alpha 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 up-regulate the expression of peroxisome proliferator-activated receptor gamma coactivator-1 beta (PGC-1 beta), an obligate cofactor for ERR alpha activity. PGC-1 beta knockdown in breast cancer cells impaired ERR alpha signaling and reduced cell proliferation, implicating a functional role for PGC-1 beta/ERR alpha in the pathogenesis of breast cancers.