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

F. Citron, I. Segatto, G.L.R. Vinciguerra, L. Musco, Francesca Russo, G. Mungo, S. D'Andrea, M.C. Mattevi, T. Perin, M. Schiappacassi, S. Massarut, C. Marchini, A. Amici, A. Vecchione, G. Baldassarre, B. Belletti

Research output: Contribution to journalArticlepeer-review

Abstract

miR-223 is an anti-inflammatory miRNA that in cancer acts either as an oncosuppressor or oncopromoter, in a context-dependent manner. In breast cancer, we demonstrated that it dampens the activation of the EGF pathway. However, little is known on the role of miR-223 during breast cancer onset and progression. miR-223 expression was decreased in breast cancer 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 three-dimensional context. In the MMTV-Δ16HER2 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 breast cancer 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 patients with luminal and HER2-positive breast cancer. 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. Significance: miR-223 may represent a predictive biomarker of response to CDK4/6 inhibitors and its loss could identify DCIS lesions that are likely to progress into invasive breast cancer. © 2019 American Association for Cancer Research.
Original languageEnglish
Pages (from-to)1064-1077
Number of pages14
JournalCancer Res.
Volume80
Issue number5
DOIs
Publication statusPublished - 2020

Keywords

  • cyclin dependent kinase 4
  • cyclin dependent kinase 6
  • epidermal growth factor receptor 2
  • microRNA 223
  • palbociclib
  • transcription factor E2F1
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • breast cancer
  • breast cancer cell line
  • breast carcinogenesis
  • cancer prognosis
  • cancer resistance
  • cell proliferation
  • controlled study
  • down regulation
  • female
  • human
  • human cell
  • human epidermal growth factor receptor 2 positive breast cancer
  • human tissue
  • in vitro study
  • in vivo study
  • intraductal carcinoma
  • luminal breast cancer
  • malignant transformation
  • molecularly targeted therapy
  • mouse
  • nonhuman
  • oncogene
  • overall survival
  • priority journal
  • tumor growth

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