title: ERRγ target genes are poor prognostic factors in Tamoxifen-treated breast cancer.
abstract: BACKGROUND
  One-third of estrogen (ER+) and/or progesterone receptor-positive (PGR+) breast tumors treated with Tamoxifen (TAM) do not respond to initial treatment, and the remaining 70% are at risk to relapse in the future. Estrogen-related receptor gamma (ESRRG, ERRγ) is an orphan nuclear receptor with broad, structural similarities to classical ER that is widely implicated in the transcriptional regulation of energy homeostasis. We have previously demonstrated that ERRγ induces resistance to TAM in ER+ breast cancer models, and that the receptor's transcriptional activity is modified by activation of the ERK/MAPK pathway. We hypothesize that hyper-activation or over-expression of ERRγ induces a pro-survival transcriptional program that impairs the ability of TAM to inhibit the growth of ER+ breast cancer. The goal of the present study is to determine whether ERRγ target genes are associated with reduced distant metastasis-free survival (DMFS) in ER+ breast cancer treated with TAM.
  
  
  METHODS
  Raw gene expression data was obtained from 3 publicly available breast cancer clinical studies of women with ER+ breast cancer who received TAM as their sole endocrine therapy. ERRγ target genes were selected from 2 studies that published validated chromatin immunoprecipitation (ChIP) analyses of ERRγ promoter occupancy. Kaplan-Meier estimation was used to determine the association of ERRγ target genes with DMFS, and selected genes were validated in ER+, MCF7 breast cancer cells that express exogenous ERRγ.
  
  
  RESULTS
  Thirty-seven validated receptor target genes were statistically significantly altered in women who experienced a DM within 5 years, and could classify several independent studies into poor vs. good DMFS. Two genes (EEF1A2 and PPIF) could similarly separate ER+, TAM-treated breast tumors by DMFS, and their protein levels were measured in an ER+ breast cancer cell line model with exogenous ERRγ. Finally, expression of ERRγ and these two target genes are elevated in models of ER+ breast cancer with hyperactivation of ERK/MAPK.
  
  
  CONCLUSIONS
  ERRγ signaling is associated with poor DMFS in ER+, TAM-treated breast cancer, and ESRRG, EEF1A2, and PPIF comprise a 3-gene signaling node that may contribute to TAM resistance in the context of an active ERK/MAPK pathway.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, 20057, USA. subha.madhavan@georgetown.edu.
authors.forename: Subha
authors.initials: S
authors.lastname: Madhavan
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, 20057, USA. yg63@georgetown.edu.
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Gusev
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, 20057, USA. ssingh@primate.wisc.edu.
authors.forename: Salendra
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, 20057, USA. rbr7@georgetown.edu.
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Riggins
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D019295:Computational Biology / Q000379:methods; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D058977:Molecular Sequence Annotation; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000378:metabolism*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D018931:Antineoplastic Agents, Hormonal; C490917:ESRRG protein, human; D011960:Receptors, Estrogen; D013629:Tamoxifen