Estrogen Mediated-Activation of miR-191/425 Cluster Modulates Tumorigenicity of Breast Cancer Cells Depending on Estrogen Receptor Status

Abstract

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.

MicroRNA screening identifies circulating microRNAs as potential biomarkers for osteosarcoma

“…Similarly, miR-20a is downregulated in hepatocellular carcinoma (HCC) and correlated with HCC recurrence and poor prognosis (36). In addition, miR-425 is able to reduce proliferation, impair tumorigenesis and metastasis, and increase expression of epithelial markers in aggressive breast cancer cells by targeting SATB homeobox 1, CCND2 and Fascin actin-bundling protein 1 (37). The tumor suppressive role of miR-16 was also confirmed by in vitro and in vivo functional experiments associated with OS (26).…”

Noncoding RNAs in breast cancer

“…The tumor suppressor cylindromatosis (CYLD), targeted by miR-181 b, is a deubiquitinating enzyme that inhibits the NFjB and mitogenactivated protein kinase (MAPK) activation pathways by deubiquitinating upstream regulatory factors [68,128]. Early growth response gene 1 (EGR1) is a tumor-suppressive transcription factor involved in mediating hormone starvation-induced apoptosis in ER-positive breast cancer cells [72]. Through targeting EGR1, miR-191 protects ER-positive breast cancer cells from apoptosis induced by hormone deprivation [72].…”

“…Early growth response gene 1 (EGR1) is a tumor-suppressive transcription factor involved in mediating hormone starvation-induced apoptosis in ER-positive breast cancer cells [72]. Through targeting EGR1, miR-191 protects ER-positive breast cancer cells from apoptosis induced by hormone deprivation [72]. FOXO1 and FOXO3a, targeted by miR-96 and miR-182, are two well-known forkhead box-containing transcription factors with tumor-suppressive roles in regulating cell cycle progression, DNA repair and apoptosis [63,64].…”

SATB1 overexpression promotes malignant T-cell proliferation in cutaneous CD30+ lymphoproliferative disease by repressing p21

“…31,32 To test whether epigenetic mechanisms contribute to the SATB1 upregulation during disease progression, we treated Mac-1 cells with DNA methylation inhibitor DAC or histone deacetylase inhibitor TSA and found marked SATB1 upregulation upon DNA demethylation, rather than histone deacetylase inhibition ( Figure 6A). There were several CpG dinucleotide-rich regions around and upstream of SATB1 TSS locus.…”