Estrogen-Related Receptors Gene Expression and Copy Number Alteration Association With the Clinicopathologic Characteristics of Breast Cancer.

Purpose: It has been suggested that dysregulation of transcription factors expression or activity plays significant roles in breast cancer (BC) severity and poor prognosis. Therefore, our study aims to thoroughly evaluate the estrogen-related receptor isoforms (ESRRs) expression and copy number alteration (CNA) status and their association with clinicopathologic characteristics in BC.

Methods: A METABRIC dataset consist of 2509 BC patients' samples was obtained from the cBioPortal public domain. The gene expression, putative CNA, and relevant tumor information of ESRRs were retrieved. ESRRs messenger RNA (mRNA) expression in BC cell lines was obtained from the Cancer Cell Line Encyclopedia (CCLE). Association and correlation analysis of ESRRs expression with BC clinicopathologic characteristics and molecular subtype were performed. Kaplan-Meier survival analysis was conducted to evaluate the prognostic value of ESRRs expression on patient survival.

Results: ESRRα expression correlated negatively with patients' age and overall survival, whereas positively correlated with tumor size, the number of positive lymph nodes, and Nottingham prognostic index (NPI). Conversely, ESRRγ expression was positively correlated with patients' age and negatively correlated with NPI. ESRRα and ESRRγ expression were significantly associated with tumor grade, expression of hormone receptors, human epidermal growth factor receptor 2 (HER2), and molecular subtype, whereas ESRRβ was only associated with tumor stage. A significant and distinct association of each of ESRRs CNA with various clinicopathologic and prognostic factors was also observed. Kaplan-Meier survival analysis demonstrated no significant difference for survival curves among BC patients with high or low expression of ESRRα, β, or γ. On stratification, high ESRRα expression significantly reduced survival among premenopausal patients, patients with grade I/II, and early-stage disease. In BC cell lines, only ESRRα expression was significantly higher in HER2-positive cells. No significant association was observed between ESRRβ expression and any of the clinicopathologic characteristics examined.

Conclusions: In this clinical dataset, ESRRα and ESRRγ mRNA expression and CNA show a significant correlation and association with distinct clinicopathologic and prognostic parameters known to influence treatment outcomes; however, ESRRβ failed to show a robust role in BC pathogenesis. ESRRα and ESRRγ can be employed as therapeutic targets in BC-targeted therapy. However, the role of ESRRβ in BC pathogenesis remains unclear.