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Oncogene. 2018 Aug 9. doi: 10.1038/s41388-018-0445-3. [Epub ahead of print]

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

Author information

1
Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia (IIT), 20139, Milan, Italy. paola.bonetti@iit.it.
2
Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia (IIT), 20139, Milan, Italy.
3
IFOM, the FIRC Institute for Molecular Oncology Foundation, 20139, Milan, Italy.
4
Department of Experimental Oncology, European Institute of Oncology (IEO), 20100, Milan, Italy.
5
Dipartimento di Scienze della Salute, Università degli Studi di Milano, 20100, Milan, Italy.
6
Memorial Sloan-Kettering Cancer Center (MSKCC), New York, USA.
7
Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia (IIT), 20139, Milan, Italy. francesco.nicassio@iit.it.

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.

PMID:
30093634
DOI:
10.1038/s41388-018-0445-3

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