MicroRNAs (miRNAs) act as negative regulators of gene expression in the cytoplasm. Previous studies identified miRNAs associated with the spliceosome. Here we study three breast-derived cell-lines with increased tumorigenicity (from MCF-10A to MCF-7 and MDA-MB-231) and compared their miRNA sequences at the spliceosome fraction (SF). We report that the SF-miRNAs expression, identity, and pre-miRNA segmental composition vary across these cell-lines. The expression of the majority of the abundant

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... F-miRNAs (e.g. miR-100, miR-30a, and let-7 members) shows an opposite trend in view of the literature and breast cancer large cohorts. The results suggest that SF-miRNAs act in the nucleus on alternative targets than in the cytoplasm. One such miRNA is miR-7704 whose genomic position overlaps HAGLR, a cancer-related lncRNA. We found an inverse expression of miR-7704 and HAGLR in the tested cell lines. Moreover, inhibition of miR-7704 caused an increase in HAGLR expression. Furthermore, increasing miR-7704 levels attenuated the MDA-MB-231 cell-division rate. While miR-7704 acts as oncomiR in breast cancer patients, it has a tumor-suppressing function in SF, with HAGLR being its nuclear target. Manipulating miR-7704 levels is a potential lead for altering tumorigenicity. Altogether, we report on the potential of manipulating SF-miRNAs as an unexplored route for breast cancer therapeutics.