Simple SummaryGAS5is a lncRNA that was identified decades ago as a key player in arresting the growth of mouse fibroblasts.GAS5may 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.GAS5expression 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),GAS5has mainly been described as tumor suppressor lncRNA capable of promoting apoptosis and inhibiting cell proliferation. Low expression ofGAS5is 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 ofGAS5may have important translational implications in BC as well as in other malignancies.AbstractThe lncRNAGAS5plays a significant role in tumorigenicity and progression of breast cancer (BC). In this review, we first summarize the role ofGAS5in cell biology, focusing on its expression data in human normal tissues. We present data onGAS5expression in human BC tissues, highlighting its downregulation in all major BC classes. The main findings regarding the molecular mechanisms underlyingGAS5dysregulation are discussed, including DNA hypermethylation of the CpG island located in the promoter region of the gene. We focused on the action ofGAS5as 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 ofGAS5in BC. We discuss the current knowledge on the role ofGAS5as candidate prognostic factor, a responsive molecular therapeutic target, and a circulating biomarker in liquid biopsies with clinical importance in BC. The findings positionGAS5as 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.