The Orphan Nuclear Receptor Estrogen-Related Receptor Beta in Triple-Negative Breast Cancer
Fernandez, Aileen I
Riegel, Anna T
Triple negative breast cancer (TNBC)/ basal-like breast cancer (BLBC) is a highly aggressive form of breast cancer. 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 expression, DNA copy number levels, and protein expression with demographic, clinicopathological, and gene expression features in breast tumor clinical specimens.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.ESRRB mRNA expression is significantly lower in patients with 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 and that distinct patterns of ERRβ isoform subcellular localization are key features in TNBC/BLBC.
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Jackson, Devin Eugene (Georgetown University, 2021)Breast cancer is the most frequently diagnosed and the second most fatal cancer for women in America. Most breast cancer-related mortality is due to metastatic disease. However, despite the importance of metastasis for ...