Abstract C103: ERRβ: Validating a novel target for triple-negative breast cancer

Abstract

Abstract Triple-negative breast cancer (TNBC)—defined as estrogen receptor- (ER), progesterone receptor- (PR), and human epidermal growth factor receptor 2- (HER2) negative—is a highly aggressive form of breast cancer prevalent in African-American (AA) women. Current treatment strategies rely on cytotoxic chemotherapy because ER- and HER2-targeted therapies are ineffective in TNBC, leaving a tremendous need for new effective therapies with less toxicity. Nuclear receptors are highly druggable targets. Classical examples include ligand-regulated receptors like ER, but there is opportunity for orphan nuclear receptors (ONR) to be studied as potential targets for cancer therapy. Our lab has published that increased mRNA expression of ONR estrogen-related receptor beta (ERRβ, gene symbol ESRRB) correlates with better recurrence- and distant metastasis-free survival in women with TNBC/basal-like breast cancer. We also showed that treatment with a small-molecule agonist ligand for ERRβ (DY131) has growth-inhibitory and antimitotic activity in TNBC cell lines. The goal of our current work is to comprehensively characterize ERRβ copy number, mRNA, protein expression, and ERRβ function in TNBC. ESRRB copy number was determined in 106 primary breast tumors (TNBC n=56, nonTNBC n=50) by Agilent SurePrint G3 Human CGH Microarray in a cohort AA and Caucasian (CA) women. ESRRB mRNA expression was determined in The Cancer Genome Atlas (TCGA) Breast Cancer RNAseq data. Association of ESRRB mRNA with overall survival was determined in Illumina gene expression array data from METABRIC. ERR protein expression is being assessed by immunohistochemistry (IHC) in a tissue microarray of 150 primary breast tumors (50 TNBC, 50 ER+, 50 HER2+). Ongoing studies are focusing on genetic modification of cell lines, specifically the overexpression of ERRβ in nontransformed mammary epithelial and TNBC cell lines. DNA: In both TNBC and nonTNBC, AA patients had a markedly higher frequency of ESRRB copy number loss than CA patients (2 *p=0.012 for TNBC, p=0.052 for nonTNBC). RNA: In TCGA breast cancer patients by PAM50 subtype, TNBC/basal-like patients have significantly lower ESRRB mRNA expression than Luminal A patients (*p=0.0015). Among systemically untreated patients in the METABRIC dataset, low ESRRB mRNA is significantly associated with poor overall survival in TNBC (hazard ratio 0.24, 95% confidence interval 0.07-0.85, *p=0.016). Protein: Analysis of ERR protein expression by IHC is ongoing. Function: Focusing on overexpression of ERRβ in cell lines, we aim to analyze multiple phenotypes including cell proliferation, cell invasion and migration, and differential gene expression. Conclusions: Breast tumors from AA women are significantly more likely to have reduced ESRRB copy number vs. CA women. TNBC patients have lower ESRRB mRNA expression and low ESRRB mRNA expression predicts for poor overall survival in TNBC. These data suggest that ERRβ expression has prognostic value in breast cancer, particularly in TNBC. Citation Format: Aileen I. Fernandez, Garrett Graham, Bálazs Györffy, Luciane R. Cavalli, Rebecca B. Riggins. ERRβ: Validating a novel target for triple-negative breast cancer [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C103.