Triple-negative breast cancer (TNBC) carries a worse prognosis compared to other breast cancer subtypes due to aggressive behaviour and, most importantly, limited targeted therapies. Thus, identifying and validating new therapeutic targets for TNBC is essential for improving survival rates and overall prognosis.
The emerging development of oligonucleotide-based therapies enables us to widen the scope of possible targets to include downregulated and silenced genes. Inactivation of tumor suppressors is as crucial for malignant transformation and tumor progression as activation of oncogenes, leaving many genes challenging to target directly thus far. Long non-coding RNAs (lncRNAs) are exciting new therapeutic targets in cancer treatment due to their tissue-specific expression and dysregulation in cancer. This study aims to investigate lncRNAs as potential tumor suppressors in TNBC to identify new therapeutic target candidates.
We generated a computational pipeline using publicly available RNAseq data of patient tissues to identify significantly down-regulated lncRNAs in TNBC. This revealed a list of silenced lncRNAs in TNBC (SLINT), from which we prioritized 11 SLINTs based on their clinical relevance and potential to impact breast tumors upon reactivation. We further investigated the most promising candidate SLINT1 through functional viability assays implementing a gain-of-function (GOF) model in vitro with CRISPR activation. We observed correlation of expression of SLINT1 and its neighbouring gene in the GOF model as well as TCGA and Gtex data. To further elucidate the molecular mechanism of SLINT1, RNA sequencing was performed on the GOF model and identified 300 significantly differential expressed genes upon SLINT1 upregulation. Pathway analysis identified a number of dysregulated pathways including the upregulation of ribosome synthesis.
This study suggests the potential of the developed pipeline for identifying lncRNAs involved in tumor suppression. With further extensive validation, this pipeline may identify a novel therapeutic target in TNBC, contributing to the development of new systemic treatments.