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

Adam T. Nelczyk, Liqian Ma, Anasuya Das Gupta, Hashni Epa Vidana Gamage, Michael T. McHenry, Madeline A. Henn, Mohammed Kadiri, Yu Wang, Natalia Krawczynska, Shruti Bendre, Sisi He, Sayyed Hamed Shahoei, Zeynep Madak-Erdogan, Shih Hsuan Hsiao, Tareq Saleh, Valerie Carpenter, David A. Gewirtz, Michael J. Spinella, Erik R. Nelson

Research output: Contribution to journalArticlepeer-review


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. Specifically, elevated tumoral TLX expression was associated with prolonged recurrence-free survival and overall survival for breast cancer patients with either estrogen receptor alpha (ERα)-negative or basal-like tumors. Using two TNBC cell lines, we found that stable overexpression of TLX impairs in vitro proliferation. RNA-Seq analysis revealed that TLX reduced the expression of genes implicated in epithelial-mesenchymal transition (EMT), a cellular program known to drive metastatic progression. Indeed, TLX overexpression significantly decreased cell migration and invasion, and robustly decreased the metastatic capacity of TNBC cells in murine models. We identify SERPINB2 as a likely mediator of these effects. Taken together, our work indicates that TLX impedes 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.

Original languageEnglish (US)
Article number166515
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number11
StatePublished - Nov 1 2022


  • NR2E1
  • Nuclear receptor
  • TLX
  • Triple negative breast cancer

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology


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