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 (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 usingRNAseq 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 150patient tissue microarray series. ResultsESRRB 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. ConclusionsDecreased ESRRB mRNA expression, and distinct patterns of ERRβ isoform subcellular localization and transcription factor activity are key features in TNBC/BLBC. KeywordsTriple negative breast cancer Basal-like breast cancer Molecular subtypes Estrogen-related receptor beta ABBREVIATIONS TNBC Triple negative breast cancer BLBC Basal-like breast cancer AA African-American ESRRB Estrogen related receptor beta IHC Immunohistochemistry ER Estrogen receptor PR progesterone receptor HER2 human epidermal growth factor two CW Caucasian/White NR Nuclear receptor(s) ONR Orphan nuclear receptor

Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes

“…However, this subtype demonstrated significant overexpression of genes (FDR < 0.05; Supplementary Fig. 34) previously associated with breast cancer including casein (CSN1S1, logFC = 7.7, P adj = 0.005) 42 and Nectin-4 (PRR4, logFC = 4.1, P adj = 1.75 × 10 −8 ), Myomesin-2 (MYOM2, logFC = 2.77, P adj = 0.02) 43 , estrogen-related receptor beta (ESRRB, logFC = 2.51, P adj = 0.03) 44 and neurotrophic receptor tyrosine kinase 3 (NTRK3, logFC = 2.45, P adj = 0.04) 45 , as well as genes associated with epithelial development (SPRR2G/SPRR2E, logFC ≥ 5.4, P adj < 0.02), mucin production (MUC7, logFC = 4.7, P adj < 0.03) 46 , and metastatic potential (LOXL4, logFC = 2.63, P adj = 0.002, and SERPINE2, logFC = 2.3, P adj = 0.006) 47,48 .…”

The integration of Tgfβ and Egfr signaling programs confers the ability to lead heterogeneous collective invasion

“…The construction of the TNBC tissue microarray (TMA) containing duplicate cores from 50 patients was performed by the Histopathology and Tissue Shared Resource (HTSR) at Georgetown University. Details of the methodology, patient consent, de-identification and demographics have been previously described (20). Multiplex staining of deparaffinized and rehydrated cores was performed through sequential rounds of staining, stripping and re-probing with antibodies recognizing K14, Vimentin and E-cadherin and OPAL fluorescent secondary antibodies (Table S1) .…”