Mir-146 connects stem cell identity with metabolism and pharmacological resistance in breast cancer

Chiara Tordonato, Matteo Jacopo Marzi, Giovanni Giangreco, Stefano Freddi, Paola Bonetti, Daniela Tosoni, Pier Paolo Di Fiore, Francesco Nicassio

Research output: Contribution to journalArticlepeer-review


Although ectopic overexpression of miRNAs can influence mammary normal and cancer stem cells (SCs/CSCs), their physiological relevance remains uncertain. Here, we show that miR-146 is relevant for SC/CSC activity. MiR-146a/b expression is high in SCs/CSCs from human/mouse primary mammary tissues, correlates with the basal-like breast cancer subtype, which typically has a high CSC content, and specifically distinguishes cells with SC/CSC identity. Loss of miR-146 reduces SC/ CSC self-renewal in vitro and compromises patient-derived xenograft tumor growth in vivo, decreasing the number of tumor-initiating cells, thus supporting its pro-oncogenic function. Transcriptional analysis in mammary SC-like cells revealed that miR-146 has pleiotropic effects, reducing adaptive response mechanisms and activating the exit from quiescent state, through a complex network of finely regulated miRNA targets related to quiescence, transcription, and one-carbon pool metabolism. Consistent with these findings, SCs/CSCs display innate resistance to anti-folate chemotherapies either in vitro or in vivo that can be reversed by miR-146 depletion, unmasking a “hidden vulnerability” exploitable for the development of anti-CSC therapies.

Original languageEnglish
Article numbere202009053
JournalJournal of Cell Biology
Issue number5
Publication statusPublished - May 3 2021

ASJC Scopus subject areas

  • Cell Biology


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