Downregulation of miR-223 expression is an early event during mammary transformation and confers resistance to CDK4/6 inhibitors in luminal breast cancer

Francesca Citron, Ilenia Segatto, Gian Luca Rampioni Vinciguerra, Lorena Musco, Francesca Russo, Giorgia Mungo, Sara D'Andrea, Maria Chiara Mattevi, Tiziana Perin, Monica Schiappacassi, Samuele Massarut, Cristina Marchini, Augusto Amici, Andrea Vecchione, Gustavo Baldassarre, Barbara Belletti

Research output: Contribution to journalArticle

Abstract

miR-223 is an anti-inflammatory microRNA that in cancer acts either as an oncosuppressor or oncopromoter, in a context-dependent manner. In breast cancer (BC), we demonstrated that it dampens the activation of the EGF pathway. However, little is known on the role of miR-223 during BC onset and progression. miR-223 expression was decreased in BC of luminal and HER2 subtypes and inversely correlated with patients' prognosis. In normal luminal mammary epithelial cells miR-223 acted cell autonomously in the control of their growth and morphology in 3D-context. In the MMTV-∆16HER2 transgenic mouse model, oncogene transformation resulted in a timely abrogation of miR-223 expression, likely due to activation of E2F1, a known repressor of miR-223 transcription. Accordingly, treatment with CDK4/6 inhibitors, which eventually results in restraining E2F1 activity, restored miR-223 expression and miR-223 ablation induced luminal BC resistance to CDK4/6 inhibition, both in vitro and in vivo. Notably, miR-223 expression was lost in microdissected ductal carcinoma in situ (DCIS) from luminal and HER2-positive BC patients. Altogether, these results identify downmodulation of miR-223 as an early step in luminal breast cancer onset and suggest that it could be used to identify aggressive DCIS and predict the response to targeted therapy.
Original languageEnglish
Pages (from-to)canres.1793.2019
JournalCancer Research
DOIs
Publication statusPublished - Dec 20 2019

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