The Metabolic Regulator ERR±, a Downstream Target of HER2/IGF-1R, as a Therapeutic Target in Breast Cancer
A partir de données génomiques portant sur plus de 800 échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein, cette étude menée in vitro identifie le rôle joué par la signalisation du récepteur ERR alpha dans la pathogenèse d'un cancer du sein
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-1²), an obligate cofactor for ERR± activity. PGC-1² knockdown in breast cancer cells impaired ERR± signaling and reduced cell proliferation, implicating a functional role for PGC-1²/ERR± in the pathogenesis of breast cancers. º ERR± signature predicts relapse-free survival in multiple breast cancer cohorts º PGC-1²/ERR± signaling affects breast cancer cell proliferation º Her2 and IGF-1 signaling activate the PGC1²/ERR± axis