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.
Dual role for miR-34a in the control of early progenitor proliferation and commitment in the mammary gland and in breast cancer / P. Bonetti, M. Climent, F. Panebianco, C. Tordonato, A. Santoro, M.J. Marzi, P.G. Pelicci, A. Ventura, F. Nicassio. - In: ONCOGENE. - ISSN 0950-9232. - 38:3(2019 Jan 17), pp. 360-374.
|Titolo:||Dual role for miR-34a in the control of early progenitor proliferation and commitment in the mammary gland and in breast cancer|
|Parole Chiave:||Animals; Breast Neoplasms; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cell Self Renewal; Epithelial Cells; Female; Humans; Mammary Glands, Animal; Mesenchymal Stem Cells; Mice; Mice, Knockout; MicroRNAs; Neoplastic Stem Cells; RNA, Neoplasm; Spheroids, Cellular; Triple Negative Breast Neoplasms; Wnt Signaling Pathway|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
Settore MED/06 - Oncologia Medica
|Data di pubblicazione:||17-gen-2019|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/s41388-018-0445-3|
|Appare nelle tipologie:||01 - Articolo su periodico|