title: Perturbation of Rb, p53, and Brca1 or Brca2 cooperate in inducing metastatic serous epithelial ovarian cancer.
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.
authors.affiliation: Center for Advanced Preclinical Research, Advanced Biomedical Computing Center, SAIC at Frederick National Laboratory for Cancer Research, Mouse Cancer Genetics Program, NCI-Frederick, Frederick, Maryland 21702, USA.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Szabova
authors.forename: Chaoying
authors.initials: C
authors.lastname: Yin
authors.forename: Sujata
authors.initials: S
authors.lastname: Bupp
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Guerin
authors.forename: Jerome J
authors.initials: JJ
authors.lastname: Schlomer
authors.forename: Deborah B
authors.initials: DB
authors.lastname: Householder
authors.forename: Maureen L
authors.initials: ML
authors.lastname: Baran
authors.forename: Ming
authors.initials: M
authors.lastname: Yi
authors.forename: Yurong
authors.initials: Y
authors.lastname: Song
authors.forename: Wenping
authors.initials: W
authors.lastname: Sun
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: McDunn
authors.forename: Philip L
authors.initials: PL
authors.lastname: Martin
authors.forename: Terry
authors.initials: T
authors.lastname: Van Dyke
authors.forename: Simone
authors.initials: S
authors.lastname: Difilippantonio
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism*; D000077216:Carcinoma, Ovarian Epithelial; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009362:Neoplasm Metastasis; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53