Journal
ONCOTARGET
Volume 6, Issue 18, Pages 16638-16652Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3184
Keywords
triple negative breast cancer; RHOGDI; miRNA biogenesis; star strand; isomiRs
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Funding
- National Institutes of Health [CA125806]
- Office of Naval Research [N00014-16-1-1136]
- National Institute of General Medical Sciences of the National Institutes of Health [1 U54 GM104940, P20GM103518]
- National Center for Research Resources [P20RR020152]
- Department of Defense Breast Cancer Research Program [BC085426]
- Louisiana Clinical and Translational Science Center
- NIH
- Integrative Cancer Biology Program (ICBP [NCI-U54 CA113001-07]
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Epithelial to mesenchymal transition (EMT) involves loss of an epithelial phenotype and activation of a mesenchymal one. Enhanced expression of genes associated with a mesenchymal transition includes ZEB1/2, TWIST, and FOXC1. miRNAs are known regulators of gene expression and altered miRNA expression is known to enhance EMT in breast cancer. Here we demonstrate that the tumor suppressive miRNA family, miR-200, is not expressed in triple negative breast cancer (TNBC) cell lines and that miR-200b-3p over-expression represses EMT, which is evident through decreased migration and increased CDH1 expression. Despite the loss of migratory capacity following re-expression of miR-200b-3p, no subsequent loss of the conventional miR-200 family targets and EMT markers ZEB1/2 was observed. Next generation RNA-sequencing analysis showed that enhanced expression of primiR-200b lead to ectopic expression of both miR-200b-3p and miR-200b-5p with multiple isomiRs expressed for each of these miRNAs. Furthermore, miR-200b-5p was expressed in the receptor positive, epithelial breast cancer cell lines but not in the TNBC (mesenchymal) cell lines. In addition, a compensatory mechanism for miR-200b-3p/200b-5p targeting, where both miRNAs target the RHOGDI pathway leading to non-canonical repression of EMT, was demonstrated. Collectively, these data are the first to demonstrate dual targeting by miR-200b-3p and miR-200b-5p and a previously undescribed role for microRNA processing and strand expression in EMT and TNBC, the most aggressive breast cancer subtype.
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