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

• DOI: 10.1083/jcb.202009053
• Publication Date: 2021-04-05T17:37:45Z
• Authors: Chiara Tordonato; Matteo Jacopo Marzi; Giovanni Giangreco; Stefano Freddi; Paola Bonetti; Daniela Tosoni; Pier Paolo Di Fiore; Francesco Nicassio
• Keywords: Ectopic expression

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 high in SCs/CSCs from human/mouse primary tissues, correlates with the basal-like breast subtype, which typically has a CSC content, specifically distinguishes identity. Loss reduces self-renewal vitro compromises patient-derived xenograft tumor growth vivo, decreasing number tumor-initiating cells, thus supporting its pro-oncogenic function. Transcriptional analysis SC-like revealed pleiotropic effects, reducing adaptive response mechanisms activating exit quiescent state, through complex network finely regulated miRNA targets related to quiescence, transcription, one-carbon pool metabolism. Consistent these findings, display innate resistance anti-folate chemotherapies either or vivo be reversed by depletion, unmasking "hidden vulnerability" exploitable development anti-CSC therapies.