The orphan nuclear receptor estrogen-related receptor beta (ERRβ) in triple-negative breast cancer

Abstract

PurposeTriple negative breast cancer (TNBC)/ basal-like breast cancer (BLBC) is a highly aggressive form of breast cancer prevalent in African-American (AA) women. We previously reported that a small molecule agonist ligand for the orphan nuclear receptor estrogen-related receptor beta (ERR{beta} or ESRRB) has growth inhibitory and anti-mitotic activity in TNBC cell lines. In this study, we evaluate the association of ESRRB mRNA, copy number levels, and protein expression with demographic, clinicopathological, and gene expression features in breast tumor clinical specimens.\n\nMethodsESRRB mRNA level expression and clinical associations were analyzed using RNAseq data. Array-based comparative genomic hybridization determined ESRRB copy number in AA and Caucasian women. Transcription factor activity was measured using promoter-reporter luciferase assays in TNBC cell lines. Semi-automatic quantification of immunohistochemistry measured ERR{beta} protein expression on a 150-patient tissue microarray series.\n\nResultsESRRB mRNA expression is significantly lower in TNBC/BLBC vs. other breast cancer subtypes. There is no evidence of ESRRB copy number loss. ESRRB mRNA expression is correlated with the expression of genes associated with neuroactive ligand-receptor interaction, metabolic pathways, and deafness. These genes contain G/C-rich transcription factor binding motifs. The ESRRB message is alternatively spliced into three isoforms, which we show have different transcription factor activity in basal-like vs. other TNBC cell lines. We further show that the ERR{beta}2 and ERR{beta}sf isoforms are broadly expressed in breast tumors at the protein level.\n\nConclusionsDecreased ESRRB mRNA expression, and distinct patterns of ERR{beta} isoform subcellular localization and transcription factor activity are key features in TNBC/BLBC.