Dual role for miR-34a in the control of early progenitor proliferation and commitment in the mammary gland and in breast cancer

Oncogene. 2019 Jan;38(3):360-374. doi: 10.1038/s41388-018-0445-3. Epub 2018 Aug 9.


The role of the tumour-suppressor miR-34 family in breast physiology and in mammary stem cells (MaSCs) is largely unknown. Here, we revealed that miR-34 family, and miR-34a in particular, is implicated in mammary epithelium homoeostasis. Expression of miR-34a occurs upon luminal commitment and differentiation and serves to inhibit the expansion of the pool of MaSCs and early progenitor cells, likely in a p53-independent fashion. Mutant mice (miR34-KO) and loss-of-function approaches revealed two separate functions of miR-34a, controlling both proliferation and fate commitment in mammary progenitors by modulating several pathways involved in epithelial cell plasticity and luminal-to-basal conversion. In particular, miR-34a acts as endogenous inhibitor of the Wnt/beta-catenin signalling pathway, targeting up to nine upstream regulators at the same time, thus modulating the expansion of the MaSCs/early progenitor pool. These multiple roles of miR-34a are maintained in a model of human breast cancer, in which chronic expression of miR-34a in triple-negative mesenchymal-like cells (enriched in cancer stem cells-CSCs) could promote a luminal-like differentiation programme, restrict the CSC pool, and inhibit tumour propagation. Hence, activation of miR-34a-dependent programmes could provide a therapeutic opportunity for the subset of breast cancers, which are rich in CSCs and respond poorly to conventional therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Proliferation / physiology
  • Cell Self Renewal / physiology
  • Epithelial Cells / metabolism
  • Female
  • Humans
  • Mammary Glands, Animal / abnormalities
  • Mammary Glands, Animal / cytology*
  • Mammary Glands, Animal / metabolism
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics
  • MicroRNAs / physiology*
  • Neoplastic Stem Cells / metabolism
  • RNA, Neoplasm / physiology*
  • Spheroids, Cellular
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology
  • Wnt Signaling Pathway


  • MIRN34 microRNA, human
  • MIRN34a microRNA, mouse
  • MicroRNAs
  • RNA, Neoplasm