BRCA2 abrogation triggers a late, chronic upregulation of interferon-stimulated genes that is further potentiated by treatment with PARP inhibitors in BRCA2-deficient cells and tumors.
BRCA2 abrogation triggers a cell-intrinsic immune response via the cGAS-STING-STAT pathway, which is potentiated by PARP inhibitors, providing insight into tumor adaptation and treatment response.
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.
Reisländer et al. (Wed,) conducted a other in BRCA2-deficient cancer. PARP inhibitors (olaparib, talazoparib) vs. Solvent control / untreated was evaluated on Upregulation of interferon-stimulated genes (ISGs). BRCA2 abrogation triggers a late, chronic upregulation of interferon-stimulated genes that is further potentiated by treatment with PARP inhibitors in BRCA2-deficient cells and tumors.
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