TY - JOUR T1 - The orphan nuclear receptor estrogen-related receptor beta (ERRβ) in triple-negative breast cancer JF - bioRxiv DO - 10.1101/734632 SP - 734632 AU - Aileen I. Fernandez AU - Xue Geng AU - Krysta Chaldekas AU - Brent Harris AU - Anju Duttargi AU - V. Layne Berry AU - Deborah L. Berry AU - Akanksha Mahajan AU - Luciane R. Cavalli AU - Balázs Gyorffy AU - Ming Tan AU - Rebecca B. Riggins Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/08/13/734632.abstract N2 - Purpose Triple 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 (ERRβ 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.Methods ESRRB 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 ERRβ protein expression on a 150-patient tissue microarray series.Results ESRRB 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 ERRβ2 and ERRβsf isoforms are broadly expressed in breast tumors at the protein level.Conclusions Decreased ESRRB mRNA expression, and distinct patterns of ERRβ isoform subcellular localization and transcription factor activity are key features in TNBC/BLBC.TNBCTriple negative breast cancerBLBCBasal-like breast cancerAAAfrican-AmericanESRRBEstrogen related receptor betaIHCImmunohistochemistryEREstrogen receptorPRprogesterone receptorHER2human epidermal growth factor twoCWCaucasian/WhiteNRNuclear receptor(s)ONROrphan nuclear receptorERREstrogen related receptorsOSOverall survivalSCAN-BSweden Cancerome Analysis Network - BreastFPKMFragments Per Kilobase of transcript per Million mapped readsESR1Estrogen receptorNHGNottingham gradeNTNNon triple negative breast canceraCGHArray comparative genomic hybridizationAFRAfrican descentAMRAd mixed AmericanDEGsDifferentially expressed genesBL2Basal-like 2LARLuminal Androgen ReceptorMLMesenchymal-likeERREEstrogen related response elementSP1Specificity-protein-1TMATissue microarray ER -