Perturbation of Rb, p53, and Brca1 or Brca2 Cooperate in Inducing Metastatic Serous Epithelial Ovarian Cancer

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.
Cancer Research (Impact Factor: 9.28). 05/2012; 72(16):4141-53. DOI: 10.1158/0008-5472.CAN-11-3834
Source: PubMed

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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    • "Prohibitin can co-localize with the expressions of tumor suppressor genes, such as c-myc, c-fos, p53, and Rb (Li et al., 2011). Interestingly, c-myc, c-fos, p53, and Rb are very important in the pathogenesis of breast and ovarian cancers (Wang et al., 2010; Alshatwi et al., 2011; Kermani et al., 2011; Luparello et al., 2012; Szabova et al., 2012; Vijayaraman et al., 2012). Prohibitin might be associated with the risk of breast and ovarian cancers. "
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