LINC01235 Is an Upstream Regulator of the NFIB Gene and the Notch Pathway in Triple-Negative Breast Cancer

We identified a long non-coding RNA (lncRNA), LINC01235, with significant enrichment in luminal progenitor (LP)-like cells in triple negative breast cancer 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 impacted the ability to form organoids. A comprehensive co-expression analysis, leveraging TCGA data, revealed a distinct correlation between LINC01235 expression and the expression of NFIB, a neighboring gene encoding a transcription factor. Subsequent CRISPR knockout or ASO-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 ChIRP-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 luminal progenitor-like cells in TNBC.