Suppressive role exerted by microRNA-29b-1-5p in triple negative breast cancer through SPIN1 regulation

Rosa Drago-Ferrante, Francesca Pentimalli, Daniela Carlisi, Anna De Blasio, Christian Saliba, Shawn Baldacchino, James Degaetano, Joseph Debono, Gordon Caruana-Dingli, Godfrey Grech, Christian Scerri, Giovanni Tesoriere, Antonio Giordano, Renza Vento, Riccardo Di Fiore

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Abstract

MiR-29 family dysregulation occurs in various cancers including breast cancers. We investigated miR-29b-1 functional role in human triple negative breast cancer (TNBC) the most aggressive breast cancer subtype. We found that miR-29b-1-5p was downregulated in human TNBC tissues and cell lines. To assess whether miR-29b-1-5p correlated with TNBC regenerative potential, we evaluated cancer stem cell enrichment in our TNBC cell lines, and found that only MDA-MB-231 and BT-20 produced primary, secondary and tertiary mammospheres, which were progressively enriched in OCT4, NANOG and SOX2 stemness genes. MiR-29b-1-5p expression inversely correlated with mammosphere stemness potential, and miR-29b-1 ectopic overexpression decreased TNBC cell growth, self-renewal, migration, invasiveness and paclitaxel resistance repressing WNT/βcatenin and AKT signaling pathways and stemness regulators. We identified SPINDLIN1 (SPIN1) among predicted miR-29b-1-5p targets. Consistently, SPIN1 was overexpressed in most TNBC tissues and cell lines and negatively correlated with miR-29b-1-5p. Target site inhibition showed that SPIN1 seems to be directly controlled by miR-29b-1-5p. Silencing SPIN1 mirrored the effects triggered by miR- 29b-1 overexpression, whereas SPIN1 rescue by SPIN1miScript protector, determined the reversal of the molecular effects produced by the mimic-miR-29b-1-5p. Overall, we show that miR-29b-1 deregulation impacts on multiple oncogenic features of TNBC cells and their renewal potential, acting, at least partly, through SPIN1, and suggest that both these factors should be evaluated as new possible therapeutic targets against TNBC.

Original languageEnglish
Pages (from-to)28939-28958
Number of pages20
JournalOncotarget
Volume8
Issue number17
DOIs
Publication statusPublished - 2017

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Keywords

  • Cancer stem cells
  • MiR-29b-1
  • SPIN1
  • Triple-negative breast cancer
  • Wnt/β-catenin and Akt signaling pathways

ASJC Scopus subject areas

  • Oncology

Cite this

Drago-Ferrante, R., Pentimalli, F., Carlisi, D., De Blasio, A., Saliba, C., Baldacchino, S., Degaetano, J., Debono, J., Caruana-Dingli, G., Grech, G., Scerri, C., Tesoriere, G., Giordano, A., Vento, R., & Di Fiore, R. (2017). Suppressive role exerted by microRNA-29b-1-5p in triple negative breast cancer through SPIN1 regulation. Oncotarget, 8(17), 28939-28958. https://doi.org/10.18632/oncotarget.15960