Perturbation of Rb, p53, and Brca1 or Brca2 cooperate in inducing metastatic serous epithelial ovarian cancer.
| Autor: | Szabova L; 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., 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 |
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| Jazyk: | angličtina |
| Zdroj: | Cancer research [Cancer Res] 2012 Aug 15; Vol. 72 (16), pp. 4141-53. Date of Electronic Publication: 2012 May 22. |
| DOI: | 10.1158/0008-5472.CAN-11-3834 |
| Abstrakt: | 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. (©2012 AACR.) |
| Databáze: | MEDLINE |
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