BRCA2 abrogation triggers innate immune responses potentiated by treatment with PARP inhibitors.

Autor:	Reisländer T; Genome Stability and Tumourigenesis Group, The CR-UK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK., Lombardi EP; Institut Curie, PSL Research University, CNRS, UMR3244, F-75005, Paris, France.; Sorbonne Universités, UPMC Univ Paris 06, CNRS, UMR3244, F-75005, Paris, France., Groelly FJ; Genome Stability and Tumourigenesis Group, The CR-UK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK., Miar A; Hypoxia and Angiogenesis Group, Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, Oxford, OX3 9DS, UK., Porru M; Area of Translational Research, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy., Di Vito S; Area of Translational Research, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy., Wright B; Bioinformatics and Statistical Genetics Core, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK., Lockstone H; Bioinformatics and Statistical Genetics Core, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK., Biroccio A; Area of Translational Research, IRCCS Regina Elena National Cancer Institute, 00144, Rome, Italy., Harris A; Hypoxia and Angiogenesis Group, Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, Oxford, OX3 9DS, UK., Londoño-Vallejo A; Institut Curie, PSL Research University, CNRS, UMR3244, F-75005, Paris, France.; Sorbonne Universités, UPMC Univ Paris 06, CNRS, UMR3244, F-75005, Paris, France., Tarsounas M; Genome Stability and Tumourigenesis Group, The CR-UK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK. madalena.tarsounas@oncology.ox.ac.uk.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2019 Jul 17; Vol. 10 (1), pp. 3143. Date of Electronic Publication: 2019 Jul 17.
DOI:	10.1038/s41467-019-11048-5
Abstrakt:	Heterozygous germline mutations in BRCA2 predispose to breast and ovarian cancer. Contrary to non-cancerous cells, where BRCA2 deletion causes cell cycle arrest or cell death, tumors carrying BRCA2 inactivation continue to proliferate. Here we set out to investigate adaptation to loss of BRCA2 focusing on genome-wide transcriptome alterations. Human cells in which BRCA2 expression is inhibited for 4 or 28 days are subjected to RNA-seq analyses revealing a biphasic response to BRCA2 abrogation. The early, acute response consists of downregulation of genes involved in cell cycle progression, DNA replication and repair and is associated with cell cycle arrest in G1. Surprisingly, the late, chronic response consists predominantly of upregulation of interferon-stimulated genes (ISGs). Activation of the cGAS-STING-STAT pathway detected in these cells further substantiates the concept that BRCA2 abrogation triggers cell-intrinsic immune signaling. Importantly, we find that treatment with PARP inhibitors stimulates the interferon response in cells and tumors lacking BRCA2.
Databáze:	MEDLINE
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