Oncogenic miR-181a/b affect the DNA damage response in aggressive breast cancer

Andrea Bisso, Michela Faleschini, Federico Zampa, Valeria Capaci, Jacopo De Santa, Libero Santapia, Silvano Piazza, Vera Cappelletti, Mariagrazia Daidone, Reuven Agami, Giannino Del Sal

Research output: Contribution to journalArticlepeer-review

Abstract

Breast cancer is a heterogeneous tumor type characterized by a complex spectrum of molecular aberrations, resulting in a diverse array of malignant features and clinical outcomes. Deciphering the molecular mechanisms that fuel breast cancer development and act as determinants of aggressiveness is a primary need to improve patient management. Among other alterations, aberrant expression of microRNAs has been found in breast cancer and other human tumors, where they act as either oncogenes or tumor suppressors by virtue of their ability to finely modulate gene expression at the post-transcriptional level. In this study, we describe a new role for miR-181a/b as negative regulators of the DNA damage response in breast cancer, impacting on the expression and activity of the stress-sensor kinase ataxia telangiectasia mutated (ATM). We report that miR-181a and miR-181b were overexpressed in more aggressive breast cancers, and their expression correlates inversely with ATM levels. Moreover we demonstrate that deregulated expression of miR-181a/b determines the sensitivity of triple-negative breast cancer cells to the poly-ADP-ribose-polymerase1 (PARP1) inhibition. These evidences suggest that monitoring the expression of miR-181a/b could be helpful in tailoring more effective treatments based on inhibition of PARP1 in breast and other tumor types.

Original languageEnglish
Pages (from-to)1679-1687
Number of pages9
JournalCell Cycle
Volume12
Issue number11
DOIs
Publication statusPublished - Jun 1 2013

Keywords

  • ATM
  • BRCA1
  • BRCAness
  • Breast cancer
  • DNA damage response
  • MicroRNA
  • PARP inhibitors

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

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