Survivin contributes to DNA repair by homologous recombination in breast cancer cells - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Breast Cancer Research and Treatment Year : 2016

Survivin contributes to DNA repair by homologous recombination in breast cancer cells

Abstract

Survivin overexpression, frequently found in breast cancers and others, is associated with poor prognosis. Its dual regulation of cell division and apoptosis makes it an attractive therapeutic target but its exact functions that are required for tumor maintenance are still elusive. Sur-vivin protects cancer cells from genotoxic agents and this ability is generally assigned to a universal anti-apoptotic function. However, a specific role in cancer cell protection from DNA damage has been overlooked so far. We assessed DNA damage occurrence in Survivin-depleted breast cancer cells using cH2AX staining and comete assay. QPCR data and a gene conversion assay indicated that homologous recombination (HR) was impaired upon Survivin depletion. We conducted the analysis of Survivin and HR genes' expression in breast tumors. We revealed BRCAness phenotype of Survivin-depleted cells using cell death assays combined to PARP targeting. Survivin silencing leads to DNA double-strand breaks in breast cancer cells and functionally reduces HR. Survivin depletion decreases the transcription of a set of genes involved in HR, decreases RAD51 protein expression and impairs the endonuclease complex MUS81/EME1 involved in the resolution of Holliday junctions. Clinically, EME1, RAD51, EXO1, BLM expressions correlate with that of BIRC5 (coding for Survivin) and are of prognostic value. Functionally, Survivin depletion triggers p53 activation and sensitizes cancer cells to of PARP inhibition. We defined Survivin as a constitutive actor of HR in breast cancers, and implies that its inhibition would enhance cell vulnerability upon PARP inhibition.

Domains

Cancer
Fichier principal
Vignette du fichier
Véquaud-BCRT2016-EQ8.pdf (1.74 Mo) Télécharger le fichier
Origin : Publisher files allowed on an open archive
Loading...

Dates and versions

inserm-01273318 , version 1 (12-02-2016)

Identifiers

Cite

Eloise Véquaud, Grégoire Desplanques, Pascal Jézéquel, Philippe Juin, Sophie Barillé-Nion. Survivin contributes to DNA repair by homologous recombination in breast cancer cells. Breast Cancer Research and Treatment, 2016, 155, pp.53-63. ⟨10.1007/s10549-015-3657-z⟩. ⟨inserm-01273318⟩
170 View
181 Download

Altmetric

Share

Gmail Facebook X LinkedIn More