MiR-34a controls proliferation and plasticity of early-progenitors in the normal mammary gland and in breast cancer

The miR-34 is a tumor-suppressor miRNA family involved in various human cancers, including breast. However, the role of such miRNAs in the control of mammary stem cells (MaSCs), early-progenitors and their tumor counterparts, (CSCs) lies largely unexplored. Here, we identified miR-34a as directly regulated by TP53 in primary mouse mammospheres. Expression of miR-34a is induced upon luminal commitment and differentiation and able to inhibit the expansion of the MaSCs/early-progenitor pool in a p53-independent fashion. Loss of function approaches revealed that miR-34 negatively controls 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 negatively regulates Wnt/b-catenin signaling pathway, targeting multiple upstream regulators and, thus, modulating the expansion of the MaSCs/early-progenitor pool. These multiple roles of miR-34a were maintained in a model of human breast cancer, where chronic expression of miR-34a in triple-negative mesenchymal-like cells (enriched in CSCs) reduced tumor growth, restricted CSC pool and inhibited tumor propagation by promoting a luminal-like differentiation program.