Long noncoding RNA profiling unveils LINC00960 as unfavorable prognostic biomarker promoting triple negative breast cancer progression

Abstract

Long noncoding RNAs (lncRNAs) play a critical role in breast cancer pathogenesis, including Triple-Negative Breast Cancer (TNBC) subtype. Identifying the lncRNA expression patterns across different breast cancer subtypes could provide valuable insights into their potential utilization as disease biomarkers and therapeutic targets. In this study, we profiled lncRNA expression in 96 breast cancer cases, revealing significant differences compared to normal breast tissue. Variations across breast cancer subtypes, including Hormone Receptor-positive (HR + ), HER2-positive (HER2 + ), HER2 + HR + , and TNBC, as well as in relation to tumor grade and patients’ age at diagnosis were observed. TNBC and HER2+ subtypes showed distinct clustering, while HER2 + HR+ tumors clustered closer to HR+ tumors based on their lncRNA profiles. Our data identified numerous enriched lncRNAs in TNBC, notably the elevated expression of LINC00960, which was subsequently validated in two additional datasets. Analysis of LINC00960 expression in an independent TNBC cohort (n = 360) revealed elevated expression of LINC00960 to correlate with cell movement, invasion, proliferation, and migration functional categories. Depletion of LINC00960 significantly reduced TNBC cell viability, colony formation, migration, and three-dimensional growth, while increasing cell death. Mechanistically, transcriptomic profiling of LINC00960-depleted cells confirmed its tumor-promoting role, likely through sponging of hsa-miR-34a-5p, hsa-miR-16-5p, and hsa-miR-183-5p, leading to the upregulation of cancer-promoting genes including BMI1, KRAS, and AKT3. Our findings highlight the distinct lncRNA expression patterns in breast cancer subtypes and underscore the crucial role for LINC00960 in promoting TNBC pathogenesis, suggesting its potential utilization as a prognostic marker and therapeutic target.