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