Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
Cancer Cell. 2011 Oct 18;20(4):500-10. doi: 10.1016/j.ccr.2011.08.023.
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.
一个旨在评估雌激素相关受体 alpha(ERRα)活性的基因组特征被用来对 800 多个乳腺癌肿瘤进行分析,结果显示,受体活性升高的肿瘤患者无疾病生存时间更短。重要的是,该特征还预测了 ERRα 拮抗剂 XCT790 抑制乳腺癌细胞模型增殖的能力。通过化学基因组学方法确定,激活 Her2/IGF-1R 信号通路和随后的 C-MYC 稳定上调过氧化物酶体增殖物激活受体 γ 共激活因子 1β(PGC-1β)的表达,PGC-1β 是 ERRα 活性的必需辅助因子。乳腺癌细胞中的 PGC-1β 敲低会损害 ERRα 信号转导并减少细胞增殖,这表明 PGC-1β/ERRα 在乳腺癌的发病机制中具有功能作用。