MicroRNAs (
miRNAs), single-stranded non-coding RNAs, influence myriad biological processes that can contribute to
cancer. Although
tumor-suppressive and oncogenic functions have been characterized for some
miRNAs, the majority of
microRNAs have not been investigated for their ability to promote and modulate
tumorigenesis. Here, we established that the miR-191/425 cluster is transcriptionally dependent on the host gene, DALRD3, and that the
hormone 17β-estradiol (
estrogen or E2) controls expression of both miR-191/425 and DALRD3. MiR-191/425 locus characterization revealed that the recruitment of
estrogen receptor α (ERα) to the regulatory region of the miR-191/425-DALRD3 unit resulted in the accumulation of miR-191 and miR-425 and subsequent decrease in DALRD3 expression levels. We demonstrated that miR-191 protects ERα positive
breast cancer cells from
hormone starvation-induced apoptosis through the suppression of
tumor-suppressor EGR1. Furthermore, enforced expression of the miR-191/425 cluster in aggressive
breast cancer cells altered global gene expression profiles and enabled us to identify important
tumor promoting genes, including SATB1, CCND2, and FSCN1, as targets of miR-191 and miR-425. Finally, in vitro and in vivo experiments demonstrated that miR-191 and miR-425 reduced proliferation, impaired
tumorigenesis and
metastasis, and increased expression of epithelial markers in aggressive
breast cancer cells. Our data provide compelling evidence for the transcriptional regulation of the miR-191/425 cluster and for its context-specific biological determinants in breast
cancers. Importantly, we demonstrated that the miR-191/425 cluster, by reducing the expression of an extensive network of genes, has a fundamental impact on
cancer initiation and progression of
breast cancer cells.