Data from WNT11 Expression Is Induced by Estrogen-Related Receptor α and β-Catenin and Acts in an Autocrine Manner to Increase Cancer Cell Migration

Abstract

<div>Abstract<p>Elevated expression of the orphan nuclear receptor estrogen-related receptor α (ERRα) has been associated with a negative outcome in several cancers, although the mechanism(s) by which this receptor influences the pathophysiology of this disease and how its activity is regulated remain unknown. Using a chemical biology approach, it was determined that compounds, previously shown to inhibit canonical Wnt signaling, also inhibited the transcriptional activity of ERRα. The significance of this association was revealed in a series of biochemical and genetic experiments that show that (<i>a</i>) ERRα, β-catenin (β-cat), and lymphoid enhancer-binding factor-1 form macromolecular complexes in cells, (<i>b</i>) ERRα transcriptional activity is enhanced by β-cat expression and vice versa, and (c) there is a high level of overlap among genes previously shown to be regulated by ERRα or β-cat. Furthermore, silencing of ERRα and β-cat expression individually or together dramatically reduced the migratory capacity of breast, prostate, and colon cancer cells <i>in vitro</i>. This increased migration could be attributed to the ERRα/β-cat–dependent induction of WNT11. Specifically, using (<i>a</i>) conditioned medium from cells overexpressing recombinant WNT11 or (<i>b</i>) WNT11 neutralizing antibodies, we were able to show that this protein was the key mediator of the promigratory activities of ERRα/β-cat. Together, these data provide evidence for an autocrine regulatory loop involving transcriptional upregulation of WNT11 by ERRα and β-cat that influences the migratory capacity of cancer cells. Cancer Res; 70(22); 9298–308. ©2010 AACR.</p></div>