The nuclear receptor TLX (NR2E1) inhibits growth and progression of triple-negative breast cancer

Development of targeted therapies will be a critical step towards reducing the mortality associated with triple-negative breast cancer (TNBC). To achieve this, we searched for targets that met three criteria: (1) pharmacologically targetable, (2) expressed in TNBC, and (3) expression is prognostic in TNBC patients. Since nuclear receptors have a well-defined ligand-binding domain and are thus highly amenable to small-molecule intervention, we focused on this class of protein. Our analysis identified TLX (NR2E1) as a candidate. RNA-Seq analysis revealed that TLX reduced the expression of genes implicated in the pro-proliferative KRAS signaling pathway as well as epithelial-mesenchymal transition (EMT), a cellular program known to drive metastatic progression. Indeed, TLX overexpression significantly decreased cell proliferation, migration and invasion, and robustly decreased the metastatic capacity of TNBC cells in murine models. Taken together, our work indicates that TLX retards the progression of TNBC. Several ligands have been shown to regulate the transcriptional activity of TLX, providing a framework for the future development of this receptor for therapeutic intervention. Overall design: Overall 9 samples were analyzed from MDA-MB-231 cells. 3 replicates of control cells treated with control siRNA (CTL + siCTL). 3 replicates of TLX overexpressing cells treated with control siRNA (TLX+siCTL). 3 replicates of TLX overexpressing cells treated with an siRNA against TLX (TLX+siTLX)