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

Timo Reisländer, Emilia Puig Lombardi, Florian J. Groelly, Ana Miar, Manuela Porru, Serena Vito, Benjamin Wright, Helen Lockstone, Annamaria Biroccio, Adrian Harris, Arturo Londoño-Vallejo and Madalena Tarsounas ()
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Timo Reisländer: University of Oxford
Emilia Puig Lombardi: PSL Research University, CNRS, UMR3244
Florian J. Groelly: University of Oxford
Ana Miar: University of Oxford
Manuela Porru: Area of Translational Research, IRCCS Regina Elena National Cancer Institute
Serena Vito: Area of Translational Research, IRCCS Regina Elena National Cancer Institute
Benjamin Wright: University of Oxford
Helen Lockstone: University of Oxford
Annamaria Biroccio: Area of Translational Research, IRCCS Regina Elena National Cancer Institute
Adrian Harris: University of Oxford
Arturo Londoño-Vallejo: PSL Research University, CNRS, UMR3244
Madalena Tarsounas: University of Oxford

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11048-5

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