Abstract
We identified a long noncoding RNA, LINC01235, with significant enrichment in luminal progenitor (LP)-like cells in triple-negative breast cancer (TNBC) organoids and cell lines. Antisense-mediated knockdown or genetic knockout of LINC01235 in TNBC cell lines led to a decline in cell proliferation and adversely affected the ability to form organoids. A comprehensive co-expression analysis, leveraging The Cancer Genome Atlas data, revealed a distinct correlation between LINC01235 expression and the expression of NFIB, a neighboring gene encoding a transcription factor. Subsequent CRISPR knockout or antisense oligonucleotide-mediated knockdown studies demonstrated an upstream regulatory role of LINC01235 over NFIB. Moreover, our investigations demonstrated that LINC01235 regulates the Notch pathway through NFIB, and chromatin isolation by RNA purification followed by qPCR results indicated the direct binding of LINC01235 to the NFIB promoter. Our findings demonstrate that LINC01235 positively regulates NFIB transcription, which in turn modulates the Notch pathway, influencing LP-like cell proliferation in breast cancer progression. This study highlights a pivotal role of LINC01235 in TNBC and its potential as a therapeutic target.
Implications:
This study demonstrates the central role of LINC01235 as an upstream positive regulator of NFIB and the Notch signaling pathway to induce the production of LP-like cells in TNBC.