title: 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. Survivin 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 γH2AX 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.
authors.affiliation: CRCNA, UMR INSERM U892/CNRS 6299/Université de Nantes, Team 8 «Cell survival and tumor escape in breast cancers», Institut de Recherche en Santé de l'Université de Nantes, 8 quai Moncousu, BP 70721, 44 007, Nantes cedex 1, France.
authors.forename: Eloïse
authors.initials: E
authors.lastname: Véquaud
authors.affiliation: CRCNA, UMR INSERM U892/CNRS 6299/Université de Nantes, Team 8 «Cell survival and tumor escape in breast cancers», Institut de Recherche en Santé de l'Université de Nantes, 8 quai Moncousu, BP 70721, 44 007, Nantes cedex 1, France.
authors.forename: Grégoire
authors.initials: G
authors.lastname: Desplanques
authors.affiliation: CRCNA, UMR INSERM U892/CNRS 6299/Université de Nantes, Team 8 «Cell survival and tumor escape in breast cancers», Institut de Recherche en Santé de l'Université de Nantes, 8 quai Moncousu, BP 70721, 44 007, Nantes cedex 1, France.|Institut de Cancérologie de Nantes, Centre de lutte contre le Cancer René Gauducheau, Boulevard Jacques Monod, 44 805, Saint-Herblain-Nantes cedex, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Jézéquel
authors.affiliation: CRCNA, UMR INSERM U892/CNRS 6299/Université de Nantes, Team 8 «Cell survival and tumor escape in breast cancers», Institut de Recherche en Santé de l'Université de Nantes, 8 quai Moncousu, BP 70721, 44 007, Nantes cedex 1, France.|Institut de Cancérologie de Nantes, Centre de lutte contre le Cancer René Gauducheau, Boulevard Jacques Monod, 44 805, Saint-Herblain-Nantes cedex, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Juin
authors.affiliation: CRCNA, UMR INSERM U892/CNRS 6299/Université de Nantes, Team 8 «Cell survival and tumor escape in breast cancers», Institut de Recherche en Santé de l'Université de Nantes, 8 quai Moncousu, BP 70721, 44 007, Nantes cedex 1, France. sophie.barille@inserm.fr.
authors.forename: Sophie
authors.initials: S
authors.lastname: Barillé-Nion
mesh_terms: D064107:Aurora Kinase B / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D064199:Cdc20 Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D059765:Homologous Recombination; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011379:Prognosis; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C107489:BIRC5 protein, human; D064199:Cdc20 Proteins; C468783:H2AX protein, human; D006657:Histones; D051034:Inhibitor of Apoptosis Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; C577488:CDC20 protein, human; D064107:Aurora Kinase B
keywords: Breast cancer; DNA damage; Homologous recombination; Survivin