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.

Granulosa Cell-Specific Brca1 Loss Alone or Combined with Trp53 Haploinsufficiency and Transgenic FSH Expression Fails to Induce Ovarian Tumors

“…TP53 dysfunction is commonly associated with ovarian carcinoma, particularly in tumors associated with a germline BRCA1 mutation [62][63][64]. However, in the present study, females carrying the combined Brca1 GC−/− / Trp53 +/− mutations had no detectable ovarian or uterine tumors.…”

Report on the use of non‐clinical studies in the regulatory evaluation of oncology drugs

“…Conditional KO ⁄ conventional KO K18-Cre Ovarian cancer (64) Prostate cancer BRCA2 Brca2/Tp53 Conditional KO ⁄ conventional KO Pbsn-Cre Prostate cancer (65) Cancer Sci | …”

Three-Dimensional Ovarian and Oviductal Culture to Enhance Transgenic Animal Studies of Cancer and Prevention

“…Since the time of our funding, transgenic animal models have been published derived from the mouse OSE using Rb deletion, p53 deletion, mutant p53, and BRCA1 and BRCA2 deletion alone and in combination, thus these pathways have already been confirmed to generate tumors when occurring simultaneously in the OSE 1 . In addition, Pten deletion with KRAS was published and reported to form low grade serous tumors from mouse OSE 2 .…”