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

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.

Keywords: GAS5; breast cancer; lncRNAs; ncRNAs.

Figure 1

Human GAS5 gene locus, structure, and transcript variants. GAS5 is a lncRNA encoded by a sequence located at 1q25.1. In The Genome Browser database, 15 different RNA isoforms have been annotated with lengths of 510–725 nucleotides. GAS5 transcript isoforms include up to 13 exons. GAS5 is a gene harboring 10 small nucleolar RNA genes (snoRNA) in its introns (SNORD genes). (From Genome Browser; https://genome.ucsc.edu modified, accessed on 2 May 2023).

Figure 2

GAS5 gene expression from GTEx (Release V8). The NIH Genotype–Tissue Expression (GTEx) project (https://commonfund.nih.gov/GTEx, accessed on 26 April 2023) was created to establish a sample and data resource for studies on gene expression in multiple human tissues. This track shows the median gene expression levels in 52 tissues and two cell lines (EBV-transformed lymphocytes and cultured fibroblasts) based on RNA-seq data from the GTEx final data release (V8, August 2019) obtained from UCSC genome browser (https://genome.ucsc.edu, accessed on 26 April 2023). This release is based on data from 17,382 tissue samples obtained from 948 adult post-mortem individuals.

Figure 3

GAS5 expression levels in TCGA datasets obtained by consulting different databases. (A) GAS5 expression levels in primary BC tissues and normal tissues from TCGA datasets, evaluable in OncoDB, UALCAN, and TANRIC databases. (B) GAS5 expression levels in the BRCA dataset from UALCAN based on BC subclasses, cancer stages, and histological subtypes. IDC, infiltrating ductal carcinoma; ILC, infiltrating lobular carcinoma; Mixed, mixed histology; INOS, infiltrating carcinoma not otherwise specified. * p < 0.05.

Figure 4

Schematic representation of mechanisms involved in the regulation of GAS5 expression in BC. (A) GAS5 expression can be downregulated by DNA methylation (left). MYC silencing (right) induced by siRNA molecules can decrease GAS5 expression. Black circles indicate methylated cytosines. (B) Different pathways, including mTOR, NMD, and NOTCH-1, can be involved in the post-transcriptional regulation of GAS5 in BC. Nonsense mediated decay, NMD.