The Biological Role and Translational Implications of the Long Non-Coding RNA GAS5 in Breast Cancer

SIMPLE SUMMARY: GAS5 is a lncRNA that was identified decades ago as a key player in arresting the growth of mouse fibroblasts. GAS5 may fold into an RNA structure that competes with the intracellular glucocorticoid receptor for binding to DNA targets located on the promoters of apoptosis-associated genes, thus controlling their expression. GAS5 expression has been examined in a variety of human cancers, and its levels have been found to be lower in cancer tissues than in adjacent non-tumor tissues. In breast cancer (BC), GAS5 has mainly been described as tumor suppressor lncRNA capable of promoting apoptosis and inhibiting cell proliferation. Low expression of GAS5 is correlated with poor prognosis, and its expression is modulated by certain chemotherapeutic agents and during the acquisition of drug resistance. Due to its role and expression trend, new experimental approaches to augment or restore the cellular levels of GAS5 may have important translational implications in BC as well as in other malignancies. ABSTRACT: The lncRNA GAS5 plays a significant role in tumorigenicity and progression of breast cancer (BC). In this review, we first summarize the role of GAS5 in cell biology, focusing on its expression data in human normal tissues. We present data on GAS5 expression in human BC tissues, highlighting its downregulation in all major BC classes. The main findings regarding the molecular mechanisms underlying GAS5 dysregulation are discussed, including DNA hypermethylation of the CpG island located in the promoter region of the gene. We focused on the action of GAS5 as a miRNA sponge, which is able to sequester microRNAs and modulate the expression levels of their mRNA targets, particularly those involved in cell invasion, apoptosis, and drug response. In the second part, we highlight the translational implications of GAS5 in BC. We discuss the current knowledge on the role of GAS5 as candidate prognostic factor, a responsive molecular therapeutic target, and a circulating biomarker in liquid biopsies with clinical importance in BC. The findings position GAS5 as a promising druggable biomolecule and stimulate the development of strategies to restore its expression levels for novel therapeutic approaches that could benefit BC patients in the future.