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

Autor:	Tordonato C; European Institute of Oncology IRCCS, Milan, Italy.; Department of Oncology and Hemato-Oncology, Università Degli Studi di Milano, Milano, Italy., Marzi MJ; Center for Genomic Science of Istituto Italiano di Tecnologia at European School of Molecular Medicine, Istituto Italiano di Tecnologia, Milan, Italy., Giangreco G; European Institute of Oncology IRCCS, Milan, Italy.; Tumour Cell Biology Laboratory, The Francis Crick Institute, London, UK., Freddi S; European Institute of Oncology IRCCS, Milan, Italy., Bonetti P; Center for Genomic Science of Istituto Italiano di Tecnologia at European School of Molecular Medicine, Istituto Italiano di Tecnologia, Milan, Italy., Tosoni D; European Institute of Oncology IRCCS, Milan, Italy., Di Fiore PP; European Institute of Oncology IRCCS, Milan, Italy.; Department of Oncology and Hemato-Oncology, Università Degli Studi di Milano, Milano, Italy., Nicassio F; Center for Genomic Science of Istituto Italiano di Tecnologia at European School of Molecular Medicine, Istituto Italiano di Tecnologia, Milan, Italy.
Jazyk:	angličtina
Zdroj:	The Journal of cell biology [J Cell Biol] 2021 May 03; Vol. 220 (5).
DOI:	10.1083/jcb.202009053
Abstrakt:	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. (© 2021 Tordonato et al.)
Databáze:	MEDLINE
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