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Perturbation of Rb, p53, and Brca1 or Brca2 cooperate in inducing metastatic serous epithelial ovarian cancer.

The majority of human high-grade serous epithelial ovarian cancer (SEOC) is characterized by frequent mutations in p53 and alterations in the RB and FOXM1 pathways. A subset of human SEOC harbors a combination of germline and somatic mutations as well as epigenetic dysfunction for BRCA1/2. Using Cre-conditional alleles and intrabursal induction by Cre-expressing adenovirus in genetically engineered mice, we analyzed the roles of pathway perturbations in epithelial ovarian cancer initiation and progression. Inactivation of RB-mediated tumor suppression induced surface epithelial proliferation with progression to stage I carcinoma. Additional biallelic inactivation and/or missense p53 mutation in the presence or absence of Brca1/2 caused progression to stage IV disease. As in human SEOC, mice developed peritoneal carcinomatosis, ascites, and distant metastases. Unbiased gene expression and metabolomic profiling confirmed that Rb, p53, and Brca1/2-triple mutant tumors aligned with human SEOC, and not with other intraperitoneal cancers. Together, our findings provide a novel resource for evaluating disease etiology and biomarkers, therapeutic evaluation, and improved imaging strategies in epithelial ovarian cancer.

Pubmed ID: 22617326

Authors

  • Szabova L
  • Yin C
  • Bupp S
  • Guerin TM
  • Schlomer JJ
  • Householder DB
  • Baran ML
  • Yi M
  • Song Y
  • Sun W
  • McDunn JE
  • Martin PL
  • Van Dyke T
  • Difilippantonio S

Journal

Cancer research

Publication Data

August 15, 2012

Associated Grants

  • Agency: NCI NIH HHS, Id: HHSN261200800001E
  • Agency: PHS HHS, Id: HHSN261200800001E

Mesh Terms

  • Animals
  • BRCA1 Protein
  • BRCA2 Protein
  • Disease Models, Animal
  • Female
  • Gene Deletion
  • Immunohistochemistry
  • Mice
  • Mice, Transgenic
  • Mutation
  • Neoplasm Metastasis
  • Neoplasms, Glandular and Epithelial
  • Ovarian Neoplasms
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p53