MicroRNA100 inhibits self-renewal of breast cancer stem-like cells and breast tumor development

Cancer Res. 2014 Nov 15;74(22):6648-60. doi: 10.1158/0008-5472.CAN-13-3710. Epub 2014 Sep 12.

Abstract

miRNAs are essential for self-renewal and differentiation of normal and malignant stem cells by regulating the expression of key stem cell regulatory genes. Here, we report evidence implicating the miR100 in self-renewal of cancer stem-like cells (CSC). We found that miR100 expression levels relate to the cellular differentiation state, with lowest expression in cells displaying stem cell markers. Utilizing a tetracycline-inducible lentivirus to elevate expression of miR100 in human cells, we found that increasing miR100 levels decreased the production of breast CSCs. This effect was correlated with an inhibition of cancer cell proliferation in vitro and in mouse tumor xenografts due to attenuated expression of the CSC regulatory genes SMARCA5, SMARCD1, and BMPR2. Furthermore, miR100 induction in breast CSCs immediately upon their orthotopic implantation or intracardiac injection completely blocked tumor growth and metastasis formation. Clinically, we observed a significant association between miR100 expression in breast cancer specimens and patient survival. Our results suggest that miR100 is required to direct CSC self-renewal and differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / physiology
  • Aldehyde Dehydrogenase / analysis
  • Animals
  • Bone Morphogenetic Protein Receptors, Type II / physiology
  • Breast Neoplasms / etiology
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Chromosomal Proteins, Non-Histone / physiology
  • Female
  • Humans
  • Mice
  • MicroRNAs / physiology*
  • Neoplasm Metastasis
  • Neoplastic Stem Cells / physiology*
  • Transcription Factors / physiology

Substances

  • Chromosomal Proteins, Non-Histone
  • MIRN100 microRNA, human
  • MicroRNAs
  • SMARCD1 protein, human
  • Transcription Factors
  • Aldehyde Dehydrogenase
  • BMPR2 protein, human
  • Bone Morphogenetic Protein Receptors, Type II
  • Adenosine Triphosphatases
  • SMARCA5 protein, human