WNT11 expression is induced by ERRα and β-catenin and acts in an autocrine manner to increase cancer cell migration

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-09, Vol.70 (22), p.9298-9308
• Main Authors: Dwyer, Mary A., Joseph, James, Wade, Hilary E., Eaton, Matthew L., Kunder, Rebecca S., Kazmin, Dmitri, Chang, Ching-yi, McDonnell, Donald P.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-10-0226

Elevated expression of the orphan nuclear receptor estrogen-related receptor alpha (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 remains 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 demonstrate that (a) ERRα, β-catenin (β-cat) and Lymphoid enhancer-binding factor-1 (LEF-1) form macromolecular complexes in cells, (b) ERRα transcriptional activity is enhanced by βcat 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 both breast and prostate cancer cells in vitro . This increased migration could be attributed to the ERRα/β-cat dependent induction of WNT11. Specifically, using (a) conditioned media from cells overexpressing recombinant WNT11 or (b) WNT11 neutralizing antibodies, we were able to demonstrate 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.