TY - JOUR
T1 - The nuclear receptor TLX (NR2E1) inhibits growth and progression of triple- negative breast cancer
AU - Nelczyk, Adam T.
AU - Ma, Liqian
AU - Gupta, Anasuya Das
AU - Gamage, Hashni Epa Vidana
AU - McHenry, Michael T.
AU - Henn, Madeline A.
AU - Kadiri, Mohammed
AU - Wang, Yu
AU - Krawczynska, Natalia
AU - Bendre, Shruti
AU - He, Sisi
AU - Shahoei, Sayyed Hamed
AU - Madak-Erdogan, Zeynep
AU - Hsiao, Shih Hsuan
AU - Saleh, Tareq
AU - Carpenter, Valerie
AU - Gewirtz, David A.
AU - Spinella, Michael J.
AU - Nelson, Erik R.
N1 - This work was supported by grants from the following sources: National Cancer Institute of the National Institutes of Health (R01CA234025 to ERN, R01CA211875 to MJS, and CA260819 to DAG). Department of Defense Breast Cancer Research Program Era of Hope Scholar Award (W81XWH-20-BCRP-EOHS/BC200206 to ERN). Department of Defense Prostate Cancer Research Program Impact Award (W81XWH2110903 to MJS). American Institute for Cancer Research (713063 to ERN). LM was supported by a Julie and David Mead Endowed Graduate Student Fellowship. HEVG was supported by the NIH Chemistry-Biology Interface Training Grant (T32-GM136629). ATN was supported by the NIH Research Training Program in Toxicology and Environmental Health (T32 ES007326). MTM was the recipient of a University of Illinois School of Molecular and Cellular Biology Summer Undergraduate Research Fellowship.
This work was supported by grants from the following sources: National Cancer Institute of the National Institutes of Health ( R01CA234025 to ERN, R01CA211875 to MJS, and CA260819 to DAG). Department of Defense Breast Cancer Research Program Era of Hope Scholar Award ( W81XWH-20-BCRP-EOHS/BC200206 to ERN). Department of Defense Prostate Cancer Research Program Impact Award ( W81XWH2110903 to MJS). American Institute for Cancer Research ( 713063 to ERN). LM was supported by a Julie and David Mead Endowed Graduate Student Fellowship . HEVG was supported by the NIH Chemistry-Biology Interface Training Grant ( T32-GM136629 ). ATN was supported by the NIH Research Training Program in Toxicology and Environmental Health ( T32 ES007326 ). MTM was the recipient of a University of Illinois School of Molecular and Cellular Biology Summer Undergraduate Research Fellowship .
PY - 2022/11/1
Y1 - 2022/11/1
N2 - 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.
AB - 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.
KW - NR2E1
KW - Nuclear receptor
KW - TLX
KW - Triple negative breast cancer
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UR - http://www.scopus.com/inward/citedby.url?scp=85135703727&partnerID=8YFLogxK
U2 - 10.1016/j.bbadis.2022.166515
DO - 10.1016/j.bbadis.2022.166515
M3 - Article
C2 - 35932893
AN - SCOPUS:85135703727
SN - 0925-4439
VL - 1868
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 11
M1 - 166515
ER -