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.
MicroRNAs are small noncoding RNAs that act as posttranscriptional repressors of gene expression. A pivotal role for miRNAs in all the molecular processes driving initiation and progression of various malignancies, including breast cancer, has been described. Divergent miRNA expression between normal and neoplastic breast tissues has been demonstrated, as well as differential miRNA expression among the molecular subtypes of breast cancer. Over half of all breast cancers overexpress ERα, and several studies have shown that miRNA expression is controlled by ERα. We assessed the global change in microRNA expression after estrogen starvation and stimulation in breast cancer cells and identified that miR-191/425 and the host gene DALRD3 are positively associated to ERα-positive tumors. We demonstrated that ERα regulates the miR-191/425 cluster and verified the existence of a transcriptional network that allows a dual effect of estrogen on miR-191/425 and their host gene. We show that estrogen induction of miR-191/425 supports in vitro and in vivo the estrogen-dependent proliferation of ERα positive breast cancer cells. On the contrary, miR-191/425 cluster reprograms gene expression to impair tumorigenicity and metastatic potential of highly aggressive ERα negative breast cancer cells.