Abstract 4131: 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. Because ER- and HER2-targeted therapies are ineffective in TNBC, current treatment strategies rely on cytotoxic chemotherapy. There is a tremendous need for new approaches that can identify effective therapies with less toxicity for this devastating form of breast cancer. Nuclear receptors are highly druggable targets. Classical examples include ligand-regulated receptors like ER, but orphan nuclear receptors are also emerging as targets for cancer therapy. We recently published that increased mRNA expression of estrogen-related receptor beta (ERRβ, gene symbol ESRRB) correlates with better recurrence- and distant metastasis-free survival in women with TNBC, and that a small molecule agonist ligand for ERRβ (DY131, DY) has growth inhibitory and anti-mitotic activity in TNBC cell lines of multiple molecular subtypes. The goal of our current work is to validate ERRβ as a novel therapeutic target for TNBC in two distinct ways. First, we sought to determine whether ERRβ is correlated with survival outcome specifically in African-American (AA) women. Analysis of The Cancer Genome Atlas (TCGA) Breast Cancer RNAseq data shows that low ERRβ mRNA expression is specifically associated with poor overall survival in AA women with TNBC. This association is not observed in AA women with ER- or HER2-positive disease. We further find that while ERRβ mRNA expression is decreased in tumor vs. normal breast tissue regardless of race, this decrease is more pronounced in AA women. Ongoing studies in an independent cohort of AA and white women will determine whether this is due, in part, to copy number changes at the ERRβ locus (chromosome 14q24.3). Second, we sought to determine whether ERRβ expression could predict response to current treatment strategies commonly used in breast cancer, particularly TNBC. Using multiple combined datasets, we find that high ERRβ expression is associated with improved recurrence-free survival (RFS) in women with TNBC who received adjuvant or neoadjuvant therapy with anthracycline (e.g. doxorubicin, Adriamycin). No association between ERRβ and RFS is observed in patients treated with taxanes. Ongoing studies in TNBC cell lines seek to determine if activating ERRβ with its agonist ligand DY can enhance doxorubicin-mediated growth inhibition and cell death. Citation Format: Aileen I. Fernandez, Garrett Graham, Balázs Győrffy, Luciane Cavalli, Rebecca B. Riggins. ERRβ: Validating a novel target for triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4131. doi:10.1158/1538-7445.AM2017-4131