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

Oncotarget. 2017 Apr 25;8(17):28939-28958. doi: 10.18632/oncotarget.15960.

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.

Keywords: MiR-29b-1; SPIN1; Wnt/β-catenin and Akt signaling pathways; cancer stem cells; triple-negative breast cancer.

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Breast / pathology
  • Carcinogenesis / genetics
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Down-Regulation
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Microtubule-Associated Proteins / genetics*
  • Microtubule-Associated Proteins / metabolism
  • Nanog Homeobox Protein / metabolism
  • Neoplasm Invasiveness / genetics
  • Neoplastic Stem Cells / metabolism
  • Octamer Transcription Factor-3 / metabolism
  • Paclitaxel / pharmacology
  • Paclitaxel / therapeutic use
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • SOXB1 Transcription Factors / metabolism
  • Signal Transduction / genetics*
  • Triple Negative Breast Neoplasms / drug therapy
  • Triple Negative Breast Neoplasms / genetics*
  • Triple Negative Breast Neoplasms / pathology

Substances

  • Antineoplastic Agents, Phytogenic
  • Cell Cycle Proteins
  • MIRN29a microRNA, human
  • MicroRNAs
  • Microtubule-Associated Proteins
  • NANOG protein, human
  • Nanog Homeobox Protein
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • Phosphoproteins
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • spindlin
  • Paclitaxel