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

Cancer Cell. 2011 Dec 13;20(6):797-809. doi: 10.1016/j.ccr.2011.11.014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use
  • Apoptosis
  • BRCA1 Protein / genetics*
  • BRCA1 Protein / metabolism
  • Carcinoma / drug therapy
  • Carcinoma / genetics
  • Carcinoma / metabolism
  • Carcinoma / pathology
  • Cell Proliferation
  • Cisplatin / therapeutic use
  • Drug Resistance, Neoplasm* / genetics
  • Female
  • Gene Knockout Techniques
  • Genomic Instability
  • Keratin-8 / metabolism
  • Male
  • Mammary Neoplasms, Experimental / drug therapy
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Neoplasm Transplantation
  • Phthalazines / therapeutic use
  • Piperazines / therapeutic use
  • Protein Structure, Tertiary
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Transplantation, Heterologous
  • Tumor Burden / drug effects
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antineoplastic Agents
  • BRCA1 Protein
  • Keratin-8
  • Krt8 protein, mouse
  • Phthalazines
  • Piperazines
  • Tumor Suppressor Protein p53
  • Cisplatin
  • olaparib