When breaks get hot: inflammatory signaling in BRCA1/2-mutant cancers

Trends Cancer. 2022 Mar;8(3):174-189. doi: 10.1016/j.trecan.2021.12.003. Epub 2022 Jan 6.

Abstract

Genomic instability and inflammation are intricately connected hallmark features of cancer. DNA repair defects due to BRCA1/2 mutation instigate immune signaling through the cGAS/STING pathway. The subsequent inflammatory signaling provides both tumor-suppressive as well as tumor-promoting traits. To prevent clearance by the immune system, genomically instable cancer cells need to adapt to escape immune surveillance. Currently, it is unclear how genomically unstable cancers, including BRCA1/2-mutant tumors, are rewired to escape immune clearance. Here, we summarize the mechanisms by which genomic instability triggers inflammatory signaling and describe adaptive mechanisms by which cancer cells can 'fly under the radar' of the immune system. Additionally, we discuss how therapeutic activation of the immune system may improve treatment of genomically instable cancers.

Keywords: BRCA1; BRCA2; STING; cGAS; genomic instability; immune checkpoints; inflammation; mitosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism
  • DNA Repair / genetics
  • Genomic Instability
  • Humans
  • Inflammation / genetics
  • Neoplasms* / therapy
  • Signal Transduction / genetics

Substances

  • BRCA1 Protein
  • BRCA1 protein, human