Perturbation of Rb, P53, and Brca1 or Brca2 Cooperate in Inducing Metastatic Serous Epithelial Ovarian Cancer
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Abstract
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.
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Conditional knockout mice, using the Cre-lox system for cell type specificity, have been used to reproduce oncogenic mutations and homologous recombination defects to study ovarian cancer development and responses to clinically relevant treatments such as platinum-based drugs and PARP inhibitors.
“Conditional knockout mice, using the Cre-lox system for cell type specificity, have been used to reproduce oncogenic mutations and HR defects to study ovarian cancer development and responses to clinically relevant treatments such as platin-based drugs and PARPis (Szabova et al., 2012; Perets et al., 2013; Szabova et al., 2014; Zhai et al., 2017).”
From Three-dimensional modelling of ovarian cancer: from cell lines to organoids for discovery and personalized medicine (2022) · cites this paper as Szabova et al., 2012
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References 56 · Cited by 122
- Authors
- Szabova, L., Yin, C., Bupp, S., Guerin, T. M., Schlomer, J. J., Householder, D. B., Baran, M. L., Yi, M., Song, Y., Sun, W., McDunn, J. E., Martin, P. L., Van Dyke, T., & Difilippantonio, S.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Authors' Affiliations: 1Center for Advanced Preclinical Research, 2Advanced Biomedical Computing Center, SAIC at Frederick National Laboratory for Cancer Research, 3Mouse Cancer Genetics Program, NCI-Frederick, Frederick, Maryland; 4Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill; and 5Metabolon, Incorporated, Durham, North Carolina
- Corresponding author
- Difilippantonio, Simone
- ORCID
- Venue
- Cancer Research
- Published
- 2012-08-14
- Volume
- 72
- Issue
- 16
- Pages
- 4141-4153
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3421072
- OpenAlex
- W2130330160
- Cited by
- 122
- References
- 56
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 5 · 2022: 9 · 2021: 8 · 2020: 11 · 2019: 8 · 2018: 5 · 2017: 6 · 2016: 10 · 2015: 19 · 2014: 11 · 2013: 15 · 2012: 3
- FWCI
- 17.94
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health (HHSN261200800001C)
- University of Texas MD Anderson Cancer Center
- National Cancer Institute (HHSN261200800001E))
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- serous epithelial ovarian cancer, retinoblastoma protein, TP53 mutation, BRCA1, BRCA2, metastasis, peritoneal carcinomatosis, tumor progression, gene expression profiling, metabolite profiling, biomarkers
- MeSH terms
- Carcinoma, Ovarian Epithelial, Animals, Disease Models, Animal, Female, Immunohistochemistry, Mice, Transgenic, Mutation, Neoplasm Metastasis, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Tumor Suppressor Protein p53, Retinoblastoma Protein, Gene Deletion, BRCA1 Protein, BRCA2 Protein, Mice
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