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ERR? target genes are poor prognostic factors in Tamoxifen-treated breast cancer.

ABSTRACT: 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, ERR?) 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 ERR? 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 ERR? 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 ERR? target genes are associated with reduced distant metastasis-free survival (DMFS) in ER+ breast cancer treated with TAM.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. ERR? target genes were selected from 2 studies that published validated chromatin immunoprecipitation (ChIP) analyses of ERR? promoter occupancy. Kaplan-Meier estimation was used to determine the association of ERR? target genes with DMFS, and selected genes were validated in ER+, MCF7 breast cancer cells that express exogenous ERR?.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 ERR?. Finally, expression of ERR? and these two target genes are elevated in models of ER+ breast cancer with hyperactivation of ERK/MAPK.ERR? 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.

SUBMITTER: Madhavan S

PROVIDER: S-EPMC4436109 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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ERRγ target genes are poor prognostic factors in Tamoxifen-treated breast cancer.

Madhavan Subha S Gusev Yuriy Y Singh Salendra S Riggins Rebecca B RB

Journal of experimental & clinical cancer research : CR 20150515

<h4>Background</h4>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 resista ...[more]

PMID: 25971350

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Project description:BackgroundHonokiol (HON) inhibits epidermal growth factor receptor (EGFR) signaling and increases the activity of erlotinib, an EGFR inhibitor, in human head and neck cancers. In this study, using a bioinformatics approach and in vitro experiments, we assessed the target genes of HON against breast cancer resistance to tamoxifen (TAM).Materials and methodsMicroarray data were obtained from GSE67916 and GSE85871 datasets to identify differentially expressed genes (DEGs). DEGs common between HON-treated and TAM-resistant cells were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses and protein-protein interaction (PPI) networks were constructed. Selected genes were analyzed for genetic alterations, expression, prognostic value, and receiver operating characteristics (ROC). TAM-resistant MCF-7 (MCF-7 TAM-R) cells were generated and characterized for their resistance toward TAM. A combination of HON and TAM was used for cytotoxicity and gene expression analyses. Molecular docking was performed using the Molecular Operating Environment software.ResultsPPI network analysis revealed that FN1, FGFR2, and RET were the top three genes with the highest scores. A genetic alteration study of potential target genes revealed MMP16 and ERBB4 as the genes with the highest alterations among the breast cancer samples. Pathway enrichment analysis of FGFR2, RET, ERBB4, SOX2, FN1, and MMP16 showed that the genetic alterations herein were likely to impact the RTK-Ras pathway. The expression levels of RET, MMP16, and SOX2 were strongly correlated with prognostic power, with areas under the ROC curves (AUC) of 1, 0.8, and 0.8, respectively. The HON and TAM combination increased TAM cytotoxicity in MCF-7 TAM-R cells by regulating the expression of potential target genes ret, ERBB4, SOX2, and FN1, as well as the TAM resistance regulatory genes including HES1, VIM, PCNA, TP53, and CASP7. Molecular docking results indicated that HON tended to bind RET, ErbB4, and the receptor protein Notch1 ankyrin domain more robustly than its native ligand.ConclusionHON could overcome breast cancer resistance to TAM, potentially by targeting FGFR2, RET, ERBB4, MMP16, FN1, and SOX2. However, further studies are required to validate these results.

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ERR? target genes are poor prognostic factors in Tamoxifen-treated breast cancer.

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ERRγ target genes are poor prognostic factors in Tamoxifen-treated breast cancer.

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