let-7 regulates self renewal and tumorigenicity of breast cancer cells

Cell. 2007 Dec 14;131(6):1109-23. doi: 10.1016/j.cell.2007.10.054.


Cancers may arise from rare self-renewing tumor-initiating cells (T-IC). However, how T-IC self renewal, multipotent differentiation, and tumorigenicity are maintained remains obscure. Because miRNAs can regulate cell-fate decisions, we compared miRNA expression in self-renewing and differentiated cells from breast cancer lines and in breast T-IC (BT-IC) and non-BT-IC from 1 degrees breast cancers. let-7 miRNAs were markedly reduced in BT-IC and increased with differentiation. Infecting BT-IC with let-7-lentivirus reduced proliferation, mammosphere formation, and the proportion of undifferentiated cells in vitro and tumor formation and metastasis in NOD/SCID mice, while antagonizing let-7 by antisense oligonucleotides enhanced in vitro self renewal of non-T-IC. Increased let-7 paralleled reduced H-RAS and HMGA2, known let-7 targets. Silencing H-RAS in a BT-IC-enriched cell line reduced self renewal but had no effect on differentiation, while silencing HMGA2 enhanced differentiation but did not affect self renewal. Therefore let-7 regulates multiple BT-IC stem cell-like properties by silencing more than one target.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology*
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Drug Resistance, Neoplasm
  • Female
  • HMGA2 Protein / metabolism
  • Humans
  • Mice
  • Mice, SCID
  • MicroRNAs / physiology*
  • Neoplasm Metastasis
  • Neoplastic Stem Cells / physiology*
  • Proto-Oncogene Proteins p21(ras) / metabolism


  • HMGA2 Protein
  • MicroRNAs
  • mirnlet7 microRNA, human
  • Proto-Oncogene Proteins p21(ras)