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


Authors: Bonetti, P.; Climent, M.; Panebianco, F.; Tordonato, C.; Santoro, A.; Marzi, M. J.; Pelicci, P. G.; Ventura, A.; Nicassio, F.
Article Title: Dual role for miR-34a in the control of early progenitor proliferation and commitment in the mammary gland and in breast cancer
Abstract: 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. © 2018, The Author(s).
Journal Title: Oncogene
Volume: 38
Issue: 3
ISSN: 0950-9232
Publisher: Nature Publishing Group  
Date Published: 2019-01-01
Start Page: 360
End Page: 374
Language: English
DOI: 10.1038/s41388-018-0445-3
PUBMED: 30093634
PROVIDER: scopus
PMCID: PMC6336680
DOI/URL:
Notes: Article -- Export Date: 1 February 2019 -- Source: Scopus
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MSK Authors
  1. Andrea Ventura
    36 Ventura