Shatnawi Aymen, Ayoub Nehad M, Alkhalifa Amer E, Ibrahim Dalia R
Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, University of Charleston, Charleston, WV, USA.
Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan.
Breast Cancer (Auckl). 2022 Mar 24;16:11782234221086713. doi: 10.1177/11782234221086713. eCollection 2022.
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.
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.
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.
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.
有研究表明转录因子表达或活性失调在乳腺癌（BC）的严重程度和不良预后中起重要作用。因此，我们的研究旨在全面评估雌激素相关受体异构体（ESRRs）的表达和拷贝数改变（CNA）状态及其与BC临床病理特征的关系。
从cBioPortal公共领域获取了一个包含2509例BC患者样本的METABRIC数据集。检索了ESRRs的基因表达、推定的CNA及相关肿瘤信息。从癌症细胞系百科全书（CCLE）获取了BC细胞系中ESRRs信使核糖核酸（mRNA）的表达。对ESRRs表达与BC临床病理特征和分子亚型进行了关联和相关性分析。进行了Kaplan-Meier生存分析以评估ESRRs表达对患者生存的预后价值。
ESRRα表达与患者年龄和总生存期呈负相关，而与肿瘤大小、阳性淋巴结数量和诺丁汉预后指数（NPI）呈正相关。相反，ESRRγ表达与患者年龄呈正相关，与NPI呈负相关。ESRRα和ESRRγ表达与肿瘤分级、激素受体表达、人表皮生长因子受体2（HER2）及分子亚型显著相关，而ESRRβ仅与肿瘤分期相关。还观察到ESRRs的每种CNA与各种临床病理和预后因素之间存在显著且独特的关联。Kaplan-Meier生存分析表明，ESRRα、β或γ高表达或低表达的BC患者生存曲线无显著差异。分层分析显示，ESRRα高表达显著降低绝经前患者、I/II级患者和早期疾病患者的生存率。在BC细胞系中，仅ESRRα在HER2阳性细胞中的表达显著更高。未观察到ESRRβ表达与所检查的任何临床病理特征之间存在显著关联。
在这个临床数据集中，ESRRα和ESRRγ的mRNA表达及CNA与已知影响治疗结果的不同临床病理和预后参数显示出显著的相关性和关联；然而，ESRRβ在BC发病机制中未能显示出强大作用。ESRRα和ESRRγ可作为BC靶向治疗的治疗靶点。然而，ESRRβ在BC发病机制中的作用仍不清楚。
