BRCA1 RING Function Is Essential for Tumor Suppression but Dispensable for Therapy Resistance

Research output: Contribution to journalArticle

Authors

  • R Drost
  • P Bouwman
  • S Rottenberg
  • U Boon
  • E Schut
  • S Klarenbeek
  • C Klijn
  • I van der Heijden
  • H van der Gulden
  • E Wientjens
  • M Pieterse
  • A Catteau
  • P Green
  • E Solomon
  • J Jonkers

Colleges, School and Institutes

Abstract

Hereditary breast cancers are frequently caused by germline BRCA1 mutations. The BRCA1(C61G) mutation in the BRCA1 RING domain is a common pathogenic missense variant, which reduces BRCA1/BARD1 heterodimerization and abrogates its ubiquitin ligase activity. To investigate the role of BRCA1 RING function in tumor suppression and therapy response, we introduced the Brca1(C61G) mutation in a conditional mouse model for BRCA1-associated breast cancer. In contrast to BRCA1-deficient mammary carcinomas, tumors carrying the Brca1(C61G) mutation responded poorly to platinum drugs and PARP inhibition and rapidly developed resistance while retaining the Brca1(C61G) mutation. These findings point to hypomorphic activity of the BRCA1-C61G protein that, although unable to prevent tumor development, affects response to therapy.

Details

Original languageEnglish
Pages (from-to)797-809
Number of pages13
JournalCancer Cell
Volume20
Issue number6
Publication statusPublished - 1 Dec 2011