Back to Search
Start Over
BRCA1185delAG tumors may acquire therapy resistance through expression of RING-less BRCA1.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2016 Aug 01; Vol. 126 (8), pp. 2903-18. Date of Electronic Publication: 2016 Jul 25. - Publication Year :
- 2016
-
Abstract
- Heterozygous germline mutations in breast cancer 1 (BRCA1) strongly predispose women to breast cancer. BRCA1 plays an important role in DNA double-strand break (DSB) repair via homologous recombination (HR), which is important for tumor suppression. Although BRCA1-deficient cells are highly sensitive to treatment with DSB-inducing agents through their HR deficiency (HRD), BRCA1-associated tumors display heterogeneous responses to platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors in clinical trials. It is unclear whether all pathogenic BRCA1 mutations have similar effects on the response to therapy. Here, we have investigated mammary tumorigenesis and therapy sensitivity in mice carrying the Brca1185stop and Brca15382stop alleles, which respectively mimic the 2 most common BRCA1 founder mutations, BRCA1185delAG and BRCA15382insC. Both the Brca1185stop and Brca15382stop mutations predisposed animals to mammary tumors, but Brca1185stop tumors responded markedly worse to HRD-targeted therapy than did Brca15382stop tumors. Mice expressing Brca1185stop mutations also developed therapy resistance more rapidly than did mice expressing Brca15382stop. We determined that both murine Brca1185stop tumors and human BRCA1185delAG breast cancer cells expressed a really interesting new gene domain-less (RING-less) BRCA1 protein that mediated resistance to HRD-targeted therapies. Together, these results suggest that expression of RING-less BRCA1 may serve as a marker to predict poor response to DSB-inducing therapy in human cancer patients.
- Subjects :
- Alleles
Animals
Antineoplastic Agents pharmacology
Cisplatin pharmacology
Crosses, Genetic
DNA Damage
Drug Screening Assays, Antitumor
Female
Founder Effect
Frameshift Mutation
Genetic Engineering
Humans
Male
Mammary Neoplasms, Animal drug therapy
Mice
Mutation
Neoplasm Transplantation
Phthalazines pharmacology
Piperazines pharmacology
Poly(ADP-ribose) Polymerases metabolism
Recombination, Genetic
BRCA1 Protein genetics
Breast Neoplasms genetics
Drug Resistance, Neoplasm
Gene Deletion
Mammary Neoplasms, Animal genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 126
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 27454287
- Full Text :
- https://doi.org/10.1172/JCI70196