miR-134 in extracellular vesicles reduces triple-negative breast cancer aggression and increases drug sensitivity
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Keith O’Brien1,*, Michelle C. Lowry1,*, Claire Corcoran1, Vanesa G. Martinez1, Melissa Daly1, Sweta Rani1, William M. Gallagher2, Marek W. Radomski1, Roderick A.F. MacLeod3, Lorraine O’Driscoll1
1School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland
2Cancer Biology and Therapeutics Laboratory, Conway Institute, UCD School of Biomolecular and Biomedical Science, Dublin, Ireland
3Leibniz Institute DSMZ, German Collection of Human and Animal Cell Cultures, Braunschweig, Germany
*These authors have contributed equally to this work
Lorraine O’Driscoll, e-mail: [email protected]
Keywords: exosomes/extracellular vesicles, miRNAs, breast cancer
Received: October 06, 2014 Accepted: September 14, 2015 Published: September 24, 2015
Exosomes (EVs) have relevance in cell-to-cell communication carrying pro-tumorigenic factors that participate in oncogenesis and drug resistance and are proposed to have potential as self-delivery systems. Advancing on our studies of EVs in triple-negative breast cancer, here we more comprehensively analysed isogenic cell line variants and their EV populations, tissues cell line variants and their EV populations, as well as breast tumour and normal tissues. Profiling 384 miRNAs showed EV miRNA content to be highly representative of their cells of origin. miRNAs most substantially down-regulated in aggressive cells and their EVs originated from 14q32. Analysis of miR-134, the most substantially down-regulated miRNA, supported its clinical relevance in breast tumours compared to matched normal breast tissue. Functional studies indicated that miR-134 controls STAT5B which, in turn, controls Hsp90. miR-134 delivered by direct transfection into Hs578Ts(i)8 cells (in which it was greatly down-regulated) reduced STAT5B, Hsp90, and Bcl-2 levels, reduced cellular proliferation, and enhanced cisplatin-induced apoptosis. Delivery via miR-134-enriched EVs also reduced STAT5B and Hsp90, reduced cellular migration and invasion, and enhanced sensitivity to anti-Hsp90 drugs. While the differing effects achieved by transfection or EV delivery are likely to be, at least partly, due to specific amounts of miR-134 delivered by these routes, these EV-based studies identified miRNA-134 as a potential biomarker and therapeutic for breast cancer.
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