Oncotarget

Research Papers:

Dual regulation by microRNA-200b-3p and microRNA-200b-5p in the inhibition of epithelial-to-mesenchymal transition in triple-negative breast cancer

Lyndsay V. Rhodes, Elizabeth C. Martin, H. Chris Segar, David F. B. Miller, Aaron Buechlein, Douglas B. Rusch, Kenneth P. Nephew, Matthew E. Burow and Bridgette M. Collins-Burow _

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Oncotarget. 2015; 6:16638-16652. https://doi.org/10.18632/oncotarget.3184

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Abstract

Lyndsay V. Rhodes4,*, Elizabeth C. Martin1,*, H. Chris Segar1, David F. B. Miller3, Aaron Buechlein5, Douglas B. Rusch5, Kenneth P. Nephew3, Matthew E. Burow1,2, Bridgette M. Collins-Burow1

1Department of Medicine, Section of Hematology and Medical Oncology, Tulane University, New Orleans, LA, USA

2Department of Pharmacology, Tulane University, New Orleans, LA, USA

3Medical Sciences and Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Bloomington, IN, USA

4Department of Biological Sciences, Florida Gulf Coast University, Fort Myers, FL, USA

5Indiana University Center for Genomics and Bioinformatics, Bloomington, IN, USA

*These authors have contributed equally to this work

Correspondence to:

Bridgette M. Collins-Burow, e-mail: bcollin1@tulane.edu

Keywords: triple negative breast cancer, RHOGDI, miRNA biogenesis, star strand, isomiRs

Received: November 20, 2014     Accepted: January 23, 2015     Published: March 21, 2015

ABSTRACT

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 pri-miR-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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