BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance.

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.

[1]  P. Devilee,et al.  A targeted mouse Brca1 mutation removing the last BRCT repeat results in apoptosis and embryonic lethality at the headfold stage , 2001, Oncogene.

[2]  J. Peterse,et al.  Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer , 2007, Proceedings of the National Academy of Sciences.

[3]  Tony Hunter,et al.  Enhancement of BRCA1 E3 Ubiquitin Ligase Activity through Direct Interaction with the BARD1 Protein* , 2003, The Journal of Biological Chemistry.

[4]  Fred H. Gage,et al.  BRCA1 tumor suppression occurs via heterochromatin mediated silencing , 2011, Nature.

[5]  P. Brzovic,et al.  E2–BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin chain linkages , 2007, Nature Structural &Molecular Biology.

[6]  M. Pajic,et al.  Studying drug resistance using genetically engineered mouse models for breast cancer. , 2010, Methods in molecular biology.

[7]  D. Hanahan,et al.  Enhancing tumor-specific uptake of the anticancer drug cisplatin with a copper chelator. , 2010, Cancer cell.

[8]  A. Ashworth,et al.  Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. , 2009, The New England journal of medicine.

[9]  A. Tutt,et al.  Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial , 2010, The Lancet.

[10]  J Isola,et al.  Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations. , 1997, Cancer research.

[11]  B. Koller,et al.  Brca1 controls homology-directed DNA repair. , 1999, Molecular cell.

[12]  F. Couch,et al.  Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers , 2008, Nature.

[13]  T. Ludwig,et al.  BRCA1 Tumor Suppression Depends on BRCT Phosphoprotein Binding, But Not Its E3 Ligase Activity , 2011, Science.

[14]  Alan Ashworth,et al.  Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy , 2005, Nature.

[15]  G. Mills,et al.  Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors. , 2008, Cancer research.

[16]  Mark Robson,et al.  Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial , 2010, The Lancet.

[17]  Katia Basso,et al.  The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression , 2008, Proceedings of the National Academy of Sciences.

[18]  Stephen C. West,et al.  DNA interstrand crosslink repair and cancer , 2011, Nature Reviews Cancer.

[19]  H. Ruffner,et al.  Cancer-predisposing mutations within the RING domain of BRCA1: Loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Jos Jonkers,et al.  Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer , 2007, Proceedings of the National Academy of Sciences.

[21]  M. Jasin,et al.  Homology-directed dna repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutation. , 2001, Cancer research.

[22]  D. Adams,et al.  A High-Throughput Pharmaceutical Screen Identifies Compounds with Specific Toxicity against BRCA2-Deficient Tumors , 2009, Clinical Cancer Research.

[23]  C. Vandenberg,et al.  Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains , 2002, The EMBO journal.

[24]  M. J. van de Vijver,et al.  The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  Francis S. Collins,et al.  Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer , 1994, Nature Genetics.

[26]  D. Livingston,et al.  Functional communication between endogenous BRCA1 and its partner, BARD1, during Xenopus laevis development , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[27]  A. Ashworth,et al.  A Marker of Homologous Recombination Predicts Pathologic Complete Response to Neoadjuvant Chemotherapy in Primary Breast Cancer , 2010, Clinical Cancer Research.

[28]  E. Solomon,et al.  BRCA1 : BARD1 induces the formation of conjugated ubiquitin structures, dependent on K6 of ubiquitin, in cells during DNA replication and repair. , 2004, Human molecular genetics.

[29]  J. Jonkers,et al.  Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects , 2006, Oncogene.

[30]  Curtis C. Harris,et al.  Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis , 2001, Nature Genetics.

[31]  F. Couch,et al.  Edinburgh Research Explorer Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-mutated ovarian carcinoma , 2022 .

[32]  Jeroen de Ridder,et al.  Identification of cancer genes using a statistical framework for multiexperiment analysis of nondiscretized array CGH data , 2008, Nucleic acids research.

[33]  T. Ohta,et al.  Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[34]  A. D’Andrea,et al.  S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51. , 2002, Blood.

[35]  R. Weichselbaum,et al.  The Breast Cancer Susceptibility Gene BRCA1 Is Required for Subnuclear Assembly of Rad51 and Survival following Treatment with the DNA Cross-linking Agent Cisplatin* , 2000, The Journal of Biological Chemistry.

[36]  J. Holt,et al.  Impact of RING and BRCT Domain Mutations on BRCA1 Protein Stability, Localization and Recruitment to DNA Damage , 2010, Radiation research.

[37]  Makiko Takahashi,et al.  Prediction of breast cancer sensitivity to neoadjuvant chemotherapy based on status of DNA damage repair proteins , 2010, Breast Cancer Research.

[38]  Junjie Chen,et al.  BRCA1 and its toolbox for the maintenance of genome integrity , 2010, Nature Reviews Molecular Cell Biology.

[39]  K. A. Gelmon Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial , 2011 .

[40]  J. Jonkers,et al.  Preclinical mouse models for BRCA1-associated breast cancer , 2009, British Journal of Cancer.

[41]  L. Wessels,et al.  Cross-species comparison of aCGH data from mouse and human BRCA1- and BRCA2-mutated breast cancers , 2010, BMC Cancer.

[42]  T. Ohta,et al.  The RING Heterodimer BRCA1-BARD1 Is a Ubiquitin Ligase Inactivated by a Breast Cancer-derived Mutation* , 2001, The Journal of Biological Chemistry.

[43]  Chikashi Ishioka,et al.  Identification of breast tumor mutations in BRCA1 that abolish its function in homologous DNA recombination. , 2010, Cancer research.

[44]  Patrick Dowd,et al.  Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families , 1994, Nature Genetics.

[45]  Thomas Helleday,et al.  Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase , 2007, Nature.

[46]  B. Karlan,et al.  Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. , 2008, Cancer research.

[47]  M. King,et al.  BRCA1 RING Domain Cancer-predisposing Mutations , 2001, The Journal of Biological Chemistry.

[48]  Suhwan Chang,et al.  Expression of human BRCA1 variants in mouse ES cells allows functional analysis of BRCA1 mutations. , 2009, The Journal of clinical investigation.

[49]  Jan Lubinski,et al.  Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[50]  M. J. van de Vijver,et al.  Indicators of homologous recombination deficiency in breast cancer and association with response to neoadjuvant chemotherapy. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[51]  D. Adams,et al.  53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers , 2010, Nature Structural &Molecular Biology.

[52]  T. Ludwig,et al.  E3 ligase activity of BRCA1 is not essential for mammalian cell viability or homology-directed repair of double-strand DNA breaks , 2008, Proceedings of the National Academy of Sciences.

[53]  F. Gergely,et al.  BRCA1-independent ubiquitination of FANCD2. , 2003, Molecular cell.

[54]  M. Stratton,et al.  The genetics of breast cancer susceptibility. , 1998, Annual review of genetics.

[55]  M. Reinders,et al.  KC-SMARTR: An R package for detection of statistically significant aberrations in multi-experiment aCGH data , 2010, BMC Research Notes.

[56]  M. J. van de Vijver,et al.  An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[57]  P. Borst,et al.  High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs , 2008, Proceedings of the National Academy of Sciences.

[58]  T. Hamilton,et al.  Platinum Resistance: The Role of DNA Repair Pathways , 2008, Clinical Cancer Research.

[59]  J. Rodriguez,et al.  BARD1 Induces BRCA1 Intranuclear Foci Formation by Increasing RING-dependent BRCA1 Nuclear Import and Inhibiting BRCA1 Nuclear Export* , 2002, The Journal of Biological Chemistry.