miR-342 overexpression results in a synthetic lethal phenotype in BRCA1-mutant HCC1937 breast cancer cells

Elisabetta Crippa, Marco Folini, Marzia Pennati, Nadia Zaffaroni, Marco A. Pierotti, Manuela Gariboldi

Research output: Contribution to journalArticlepeer-review

Abstract

Expression of miR-342 has been strongly correlated with estrogen receptor (ER) status in breast cancer, where it is highest in ER-positive and lowest in triple-negative tumors. We investigated the effects of miR-342 transfection in the triple-negative breast cancer cell lines MDA-MB-231 and HCC1937, the latter carrying a germ-line BRCA1 mutation. Reconstitution of miR-342 led to caspase-dependent induction of apoptosis only in HCC1937 cells, while overexpression of wild-type BRCA1 in HCC1937 cells counteracted miR-342-mediated induction of apoptosis, suggesting that miR-342 overexpression and the lack of functional BRCA1 result in a synthetic lethal phenotype. Moreover, siRNA-mediated depletion of BRCA1 in MDA-MB-231 cells expressing the wild-type protein led to apoptosis upon transfection with miR-342. Using an in silico approach and a luciferase reporter system, we identified and functionally validated the Baculoviral IAP repeat-containing 6 gene (BIRC6), which encodes the anti-apoptotic factor Apollon/BRUCE, as a target of miR-342. In our model, BIRC6 likely acts as a determinant of the miRNA-dependent induction of apoptosis in BRCA1-mutant HCC1937 cells. Together, our findings suggest a tumor-suppressive function of miR- 342 that could be exploited in the treatment of a subset of BRCA1-mutant hereditary breast cancers.

Original languageEnglish
Pages (from-to)18594-18604
Number of pages11
JournalOncotarget
Volume7
Issue number14
DOIs
Publication statusPublished - 2016

Keywords

  • Apollon/BRUCE
  • BIRC6
  • BRCA1-mutant
  • MiR-342
  • Triple-negative breast cancer

ASJC Scopus subject areas

  • Oncology

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